Autophagy promotes immune evasion of
pancreatic cancer by degrading MHC-I

 

 

 

 

 

Authors:
Keisuke Yamamoto, Anthony Venida, Julian Yano, Douglas E. Biancur, Miwako Kakiuchi, Suprit Gupta, Albert S. W. Sohn, Subhadip Mukhopadhyay, Elaine Y. Lin, Seth J. Parker, Robert S. Banh, Joao A. Paulo, Kwun Wah Wen, Jayanta Debnath, Grace E. Kim, Joseph D. Mancias, Douglas T. Fearon, Rushika M. Perera & Alec C. Kimmelman

 

 

Abstract

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.

Reference:  Yamamoto, K., Venida, A., Yano, J. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse MHC Class I (H-2Kb) bound to SIINFEKL peptide (OVA residues 257-264), anti-mouse CD8α, anti-mouse PD-1 (CD279), and anti-mouse CTLA-4 (CD152) antibodies in this research study.

 


PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC

 

 

 

 

 

Authors:
Xiuchao Wang, Xin Li, Xunbin Wei, Haiping Jiang, Chungen Lan, Shengyu Yang, Han Wang, Yanhui Yang, Caijuan Tian, Zanmei Xu, Jiangyan Zhang, Jihui Hao & He Ren

 

 

Abstract

High expression of PD-L1 marks the poor prognosis of pancreatic ductal adenocarcinomas (PDAC). However, the regulatory mechanism of PD-L1 remains elusive. We recently reported that cancer Forkhead box protein 3 (Cancer-FOXP3 or C-FOXP3) promoted immune evasion of PDAC by recruiting Treg cells into PDAC via upregulation of CCL5. In this study, we confirmed that PD-L1 was overexpressed in PDAC samples from two independent cohorts of patients with radical resection. Moreover, C-FOXP3 was colocalized and correlated with the expression of PD-L1 in tumor cells at the mRNA and protein levels, and this finding was confirmed by the The Cancer Genome Atlas (TCGA) database. Chromatin immunoprecipitation (ChIP) revealed that C-FOXP3 directly bound to the promoter region of PD-L1 in pancreatic cancer cells. Furthermore, overexpression of C-FOXP3 activated the luciferase reporter gene under the control of the PD-L1 promoter. However, mutation of the binding motif-a completely reversed the luciferase activity. In addition, C-FOXP3-induced upregulation of PD-L1 effectively inhibited the activity of CD8+ T cells. Based on our recent finding that the CCL-5 antibody achieved a better response to PDAC models with high C-FOXP3 levels, we further demonstrated that the PD-L1 antibody strengthened the antitumor effect of CCL-5 blockade in xenograft and orthotopic mouse models with high C-FOXP3 levels. In conclusion, C-FOXP3 directly activates PD-L1 and represents a core transcription factor that mediates the immune escape of PDAC. Combined blockade of PD-L1 and CCL-5 may provide an effective therapy for patients with PDAC that have high C-FOXP3 levels.

Reference:  Wang, X., Li, X., Wei, X. et al. PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC. Sig Transduct Target Ther 5, 38 (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s anti-human PD-L1 (B7-H1) (Clone: 29E.2A3) and (Clone: 10F.9G2) as well as anti-mouse CD8α antibodies in this research study.

 


Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy

 

 

 

 

 

Authors:
Eva Pérez-Guijarro, Howard H. Yang, Romina E. Araya, Rajaa El Meskini, Helen T. Michael, Suman Kumar Vodnala, Kerrie L. Marie, Cari Smith, Sung Chin, Khiem C. Lam, Andres Thorkelsson, Anthony J. Iacovelli, Alan Kulaga, Anyen Fon, Aleksandra M. Michalowski, Willy Hugo, Roger S. Lo, Nicholas P. Restifo, Shyam K. Sharan, Terry Van Dyke, Romina S. Goldszmid, Zoe Weaver Ohler, Maxwell P. Lee, Chi-Ping Day & Glenn Merlino

 

 

Abstract

Although immunotherapy has revolutionized cancer treatment, only a subset of patients demonstrate durable clinical benefit. Definitive predictive biomarkers and targets to overcome resistance remain unidentified, underscoring the urgency to develop reliable immunocompetent models for mechanistic assessment. Here we characterize a panel of syngeneic mouse models, representing a variety of molecular and phenotypic subtypes of human melanomas and exhibiting their diverse range of responses to immune checkpoint blockade (ICB). Comparative analysis of genomic, transcriptomic and tumor-infiltrating immune cell profiles demonstrated alignment with clinical observations and validated the correlation of T cell dysfunction and exclusion programs with resistance. Notably, genome-wide expression analysis uncovered a melanocytic plasticity signature predictive of patient outcome in response to ICB, suggesting that the multipotency and differentiation status of melanoma can determine ICB benefit. Our comparative preclinical platform recapitulates melanoma clinical behavior and can be employed to identify mechanisms and treatment strategies to improve patient care.

Reference:  Pérez-Guijarro, E., Yang, H.H., Araya, R.E. et al. Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy. Nat Med (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s InVivoPlus anti-mouse CTLA-4 (CD152) (Clone: 9D9) and InVivoMAb anti-mouse PD-1 (CD279) (Clone: RMP1-14) in this research study.

 


Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

 

 

 

 

 

Authors:
Minhui Chen, Guanxi Qiao, Bonnie L. Hylander, Hemn Mohammadpour, Xiang-Yang Wang, John R. Subjeck, Anurag K. Singh & Elizabeth A. Repasky

 

 

Abstract

The abscopal effect following ionizing radiation therapy (RT) is considered to be a rare event. This effect does occur more frequently when combined with other therapies, including immunotherapy. Here we demonstrate that the frequency of abscopal events following RT alone is highly dependent upon the degree of adrenergic stress in the tumor-bearing host. Using a combination of physiologic, pharmacologic and genetic strategies, we observe improvements in the control of both irradiated and non-irradiated distant tumors, including metastatic tumors, when adrenergic stress or signaling through β-adrenergic receptor is reduced. Further, we observe cellular and molecular evidence of improved, antigen-specific, anti-tumor immune responses which also depend upon T cell egress from draining lymph nodes. These data suggest that blockade of β2 adrenergic stress signaling could be a useful, safe, and feasible strategy to improve efficacy in cancer patients undergoing radiation therapy.

Reference:  Chen, M., Qiao, G., Hylander, B.L. et al. Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation. Nat Commun 11, 1821 (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s InVivoMAb anti-mouse CD8α (Clone: 53-6.7), InVivoMAb anti-mouse CD4 (Clone: GK1.5), and anti-mouse PD-1 (Clone: RMP1-14) in this research study.

 


NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer

 

 

 

 

 

Authors:
Ge Qin, Xin Wang, Shubiao Ye, Yizhuo Li, Miao Chen, Shusen Wang, Tao Qin, Changlin Zhang, Yixin Li, Qian Long, Huabin Hu, Dingbo Shi, Jiaping Li, Kai Zhang, Qinglian Zhai, Yanlai Tang, Tiebang Kang, Ping Lan, Fangyun Xie, Jianjun Lu & Wuguo Deng

 

 

Abstract

Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.

Reference:  Qin, G., Wang, X., Ye, S. et al. NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer. Nat Commun 11, 1669 (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-L1 (B7-H1) (Clone: 10F.9G2) in this research study.

 


Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling

 

 

 

 

 

Authors:
Chuanhui Han, Zhida Liu, Yunjia Zhang, Aijun Shen, Chunbo Dong, Anli Zhang, Casey Moore, Zhenhua Ren, Changzheng Lu, Xuezhi Cao, Chun-Li Zhang, Jian Qiao & Yang-Xin Fu

 

 

Abstract

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9−/− tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Reference:  Han, C., Liu, Z., Zhang, Y. et al. Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling. Nat Immunol (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-L1 (B7-H1) (Clone: 10F.9G2) in this research study.

 


A conserved dendritic-cell regulatory program limits antitumour immunity

 

 

 

 

 

Authors:
Barbara Maier, Andrew M. Leader, Steven T. Chen, Navpreet Tung, Christie Chang, Jessica LeBerichel, Aleksey Chudnovskiy, Shrisha Maskey, Laura Walker, John P. Finnigan, Margaret E. Kirkling, Boris Reizis, Sourav Ghosh, Natalie Roy D’Amore, Nina Bhardwaj, Carla V. Rothlin, Andrea Wolf, Raja Flores, Thomas Marron, Adeeb H. Rahman, Ephraim Kenigsberg, Brian D. Brown & Miriam Merad

 

 

Abstract

Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8+ T cells. Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name ‘mature DCs enriched in immunoregulatory molecules’ (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein—a key checkpoint molecule—in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-γ and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.

Reference:  Maier, B., Leader, A.M., Chen, S.T. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature (2020). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse IL-4 (Clone: 11B11), anti-mouse CD40 (Clone: FGK4.5/ FGK45), and anti-mouse PD-L1 (B7-H1) (Clone: 10F.9G2) in this research study.

 


Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity

 

 

 

 

Authors:
Xinyue Qi, Fanlin Li, Yi Wu, Chen Cheng, Ping Han, Jieyi Wang & Xuanming Yang

 

 

Abstract

Costimulation of T cell responses with monoclonal antibody agonists (mAb-AG) targeting 4-1BB showed robust anti-tumor activity in preclinical models, but their clinical development was hampered by low efficacy (Utomilumab) or severe liver toxicity (Urelumab). Here we show that isotype and intrinsic agonistic strength co-determine the efficacy and toxicity of anti-4-1BB mAb-AG. While intrinsically strong agonistic anti-4-1BB can activate 4-1BB in the absence of FcγRs, weak agonistic antibodies rely on FcγRs to activate 4-1BB. All FcγRs can crosslink anti-41BB antibodies to strengthen co-stimulation, but activating FcγR-induced antibody-dependent cell-mediated cytotoxicity compromises anti-tumor immunity by deleting 4-1BB+ cells. This suggests balancing agonistic activity with the strength of FcγR interaction as a strategy to engineer 4-1BB mAb-AG with optimal therapeutic performance. As a proof of this concept, we have developed LVGN6051, a humanized 4-1BB mAb-AG that shows high anti-tumor efficacy in the absence of liver toxicity in a mouse model of cancer immunotherapy.

Reference:  Qi, X., Li, F., Wu, Y. et al. Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with FcγR affinity. Nat Commun 10, 2141 (2019). Retrieved from https://www.nature.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse 4-1BB (Clone: 3H3) and anti-mouse 4-1BB (CD137)(Clone: LOB12.3) in this research study.

 


ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity

 

 

 

 

Authors:
John Alec Moral, Joanne Leung, Luis A. Rojas, Jennifer Ruan, Julia Zhao, Zachary Sethna, Anita Ramnarain, Billel Gasmi, Murali Gururajan, David Redmond, Gokce Askan, Umesh Bhanot, Ela Elyada, Youngkyu Park, David A. Tuveson, Mithat Gönen, Steven D. Leach, Jedd D. Wolchok, Ronald P. DeMatteo, Taha Merghoub & Vinod P. Balachandran

 

 

Abstract

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues. Although ILC2s are found in cancers of these tissues, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8+ T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1+ TILC2s and PD-1+ T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.

Reference:  Moral, J.A., Leung, J., Rojas, L.A. et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 579, 130–135 (2020). Retrieved from https://www.nature.com/srep/

Product Highlights:

The authors used Bio X Cell’s InVivoPlus anti-mouse CD4 (Clone GK1.5), InVivoPlus anti-mouse CD8a (Clone 2.43), and InVivoPlus rat IgG2b isotype control (Clone LTF-2) antibodies in this research study.

 


Neutrophils mediate early cerebral cortical hypoperfusion in a murine model of subarachnoid haemorrhage

 

 

 

 

Authors:
Neutrophils mediate early cerebral cortical hypoperfusion in a murine model of subarachnoid haemorrhage
Axel Neulen, Tobias Pantel, Michael Kosterhon, Andreas Kramer, Sascha Kunath, Maximilian Petermeyer, Bernd Moosmann, Johannes Lotz, Sven R. Kantelhardt, Florian Ringel & Serge C. Thal

 

 

Abstract

Cerebral hypoperfusion in the first hours after subarachnoid haemorrhage (SAH) is a major determinant of poor neurological outcome. However, the underlying pathophysiology is only partly understood. Here we induced neutropenia in C57BL/6N mice by anti-Ly6G antibody injection, induced SAH by endovascular filament perforation, and analysed cerebral cortical perfusion with laser SPECKLE contrast imaging to investigate the role of neutrophils in mediating cerebral hypoperfusion during the first 24 h post-SAH. SAH induction significantly increased the intracranial pressure (ICP), and significantly reduced the cerebral perfusion pressure (CPP). At 3 h after SAH, ICP had returned to baseline and CPP was similar between SAH and sham mice. However, in SAH mice with normal neutrophil counts cortical hypoperfusion persisted. Conversely, despite similar CPP, cortical perfusion was significantly higher at 3 h after SAH in mice with neutropenia. The levels of 8-iso-prostaglandin-F2α in the subarachnoid haematoma increased significantly at 3 h after SAH in animals with normal neutrophil counts indicating oxidative stress, which was not the case in neutropenic SAH animals. These results suggest that neutrophils are important mediators of cortical hypoperfusion and oxidative stress early after SAH. Targeting neutrophil function and neutrophil-induced oxidative stress could be a promising new approach to mitigate cerebral hypoperfusion early after SAH.

Reference:  Neulen, A., Pantel, T., Kosterhon, M. et al. Neutrophils mediate early cerebral cortical hypoperfusion in a murine model of subarachnoid haemorrhage. Sci Rep 9, 8460 (2019). Retrieved from https://www.nature.com/srep/

Product Highlights:

The authors used Bio X Cell’s InVivoPlus anti-mouse Ly6G (Clone: 1A8) in this research study.

 


Blood-stage malaria parasites manipulate host innate immune responses through the induction of sFGL2

 

 

 

 

Authors: Yong Fu, Yan Ding, Qinghui Wang, Feng Zhu, Yulong Tan, Xiao Lu, Bo Guo, Qingfeng Zhang, Yaming Cao, Taiping Liu, Liwang Cui, and Wenyue Xu

 

 

Abstract

Malaria parasites suppress host immune responses to facilitate their survival, but the underlying mechanism remains elusive. Here, we found that blood-stage malaria parasites predominantly induced CD4+Foxp3+CD25+ regulatory T cells to release soluble fibrinogen-like protein 2 (sFGL2), which substantially enhanced the infection. This was attributed to the capacity of sFGL2 to inhibit macrophages from releasing monocyte chemoattractant protein-1 (MCP-1) and to sequentially reduce the recruitment of natural killer/natural killer T cells to the spleen and the production of interferon-γ. sFGL2 inhibited c-Jun N-terminal kinase phosphorylation in the Toll-like receptor 2 signaling pathway of macrophages dependent on FcγRIIB receptor to release MCP-1. Notably, sFGL2 were markedly elevated in the sera of patients with malaria, and recombinant FGL2 substantially suppressed Plasmodium falciparum from inducing macrophages to release MCP-1. Therefore, we highlight a previously unrecognized immune suppression strategy of malaria parasites and uncover the fundamental mechanism of sFGL2 to suppress host innate immune responses.

Reference:  YONG FU, YAN DING, QINGHUI WANG, FENG ZHU, YULONG TAN, XIAO LU, BO GUO, QINGFENG ZHANG, YAMING CAO, TAIPING LIU, LIWANG CUI, WENYUE XU. SCIENCE ADVANCES FEB 2020: EAAY9269. Retrieved from https://advances.sciencemag.org/

Product Highlights:

The authors used Bio X Cell’s anti-mouse IFNγ (Clone: XMG1.2), anti-mouse/human/rat CCL2 (MCP-1) (Clone: 2H5), anti-mouse NK1.1 (Clone: PK136), and anti-mouse CD25 (IL-2Rα)(Clone: PC-61.5.3) in this research study.

 


Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumorpromoting properties

 

 

 

 

Authors: Yuya Terashima, Etsuko Toda, Meiji Itakura, Mikiya Otsuji, Sosuke Yoshinaga, Kazuhiro Okumura, Francis H. W. Shand, Yoshihiro Komohara, Mitsuhiro Takeda, Kana Kokubo, Ming-Chen Chen, Sana Yokoi, Hirofumi Rokutan, Yutaka Kofuku, Koji Ohnishi, Miki Ohira, Toshihiko Iizasa, Hirofumi Nakano, Takayoshi Okabe, Hirotatsu Kojima, Akira Shimizu, Shiro Kanegasaki, Ming-Rong Zhang, Ichio Shimada, Hiroki Nagase, Hiroaki Terasawa & Kouji Matsushima

 

 

Abstract

Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy.

Reference:  Terashima, Y., Toda, E., Itakura, M. et al. Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties. Nat Commun 11, 609 (2020). Retrieved from https://www.nature.com/
Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-1 (CD279) (Clone: J43) in this research study.

 


Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy

 

 

 

 

Authors: Meenu Sharma, Hiep Khong, Faisal Fa’ak, Salah-Eddine Bentebibel, Louise M. E. Janssen, Brent C. Chesson, Caitlin A. Creasy, Marie-Andrée Forget, Laura Maria S. Kahn, Barbara Pazdrak, Binisha Karki, Yared Hailemichael, Manisha Singh, Christina Vianden, Srinivas Vennam, Uddalak Bharadwaj, David J. Tweardy, Cara Haymaker, Chantale Bernatchez, Shixia Huang, Kimal Rajapakshe, Cristian Coarfa, Michael E. Hurwitz, Mario Sznol, Patrick Hwu, Ute Hoch, Murali Addepalli, Deborah H. Charych, Jonathan Zalevsky, Adi Diab & Willem W. Overwijk

 

 

Abstract

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.

Reference:  Sharma, M., Khong, H., Fa’ak, F. et al. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nat Commun 11, 661 (2020). Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-1 (CD279) (Clone: RMP1-14), anti-mouse CD40 (Clone: FGK4.5/ FGK45), anti-mouse CTLA-4 (CD152) (Clone: UC10-4F10-11), anti-mouse IFNγ (Clone: XMG1.2), anti-mouse TNFα (Clone: XT3.11), and anti-mouse CD8α (Clone: YTS 169.4) in this research study.

 


 

Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity

 

 

 

 

Authors: Mubeen M. Mosaheb, Elena Y. Dobrikova, Michael C. Brown, Yuanfan Yang, Jana Cable, Hideho Okada, Smita K. Nair, Darell D. Bigner, David M. Ashley & Matthias Gromeier

 

 

Abstract

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.

Reference:  Mosaheb, M.M., Dobrikova, E.Y., Brown, M.C. et al. Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity. Nat Commun 11, 524 (2020). Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse CD8α (Clone: 2.43) this research study.

 


Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1

Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1

 

 

 

 

Authors: Caroline Imbert, Anne Montfort, Marine Fraisse, Elie Marcheteau, Julia Gilhodes, Elodie Martin, Florie Bertrand, Marlène Marcellin, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Virginie Garcia, Stéphane Carpentier, Sophie Tartare-Deckert, Pierre Brousset, Philippe Rochaix, Florent Puisset, Thomas Filleron, Nicolas Meyer, Laurence Lamant, Thierry Levade, Bruno Ségui, Nathalie Andrieu-Abadie & Céline Colacios

 

 

Abstract

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.

Reference:  Imbert, C., Montfort, A., Fraisse, M. et al. Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1. Nat Commun 11, 437 (2020). Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse CTLA-4 (CD152) (Clone: 9H10), anti-mouse PD-1 (CD279) (Clone: RMP1-14), and rat IgG2a isotype control, anti-trinitrophenol (Clone: 2A3) in this research study.

 


Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment

Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment

 

 

 

 

Authors: Naoki Horikawa, Kaoru Abiko, Noriomi Matsumura, Tsukasa Baba, Junzo Hamanishi, Ken Yamaguchi, Ryusuke Murakami, Mana Taki, Masayo Ukita, Yuko Hosoe, Masafumi Koshiyama, Ikuo Konishi & Masaki Mandai

 

 

Abstract

Background

The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy.

Methods

The frequencies of immune cell populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. The expression profiles of both the proteins and genes in the resistant tumours were analysed. The impact of granulocyte–monocyte colony-stimulating factor (GM-CSF) expression on myeloid-derived suppressor cell (MDSC) function in the resistant tumours was evaluated.

Results

We found a marked increase and reduction in the number of Gr-1 + MDSCs and CD8 + lymphocytes in the resistant tumour, and the MDSCs preferentially infiltrated the hypoxic region. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. GM-CSF promoted migration and differentiation of MDSCs, which inhibited the CD8 + lymphocyte proliferation. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case.

Conclusions

The anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers.

Reference:  Horikawa, N., Abiko, K., Matsumura, N. et al. Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment. Br J Cancer (2020). Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse GM-CSF (Clone: MP1-22E9) in this research study.

 


Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance

 

 

 

 

 

Authors: Hannah E. Dobson, Lucas Dos Santos Dias, Elaine M. Kohn, Scott Fites, Darin L. Wiesner, Thamotharampillai Dileepan, Gregory C. Kujoth, Ambily Abraham, Gary R. Ostroff, Bruce S. Klein & Marcel Wüthrich

 

 

Abstract

Priming at the site of natural infection typically elicits a protective T cell response against subsequent pathogen encounter. Here, we report the identification of a novel fungal antigen that we harnessed for mucosal vaccination and tetramer generation to test whether we can elicit protective, antigen-specific tissue-resident memory (Trm) CD4+ T cells in the lung parenchyma. In contrast to expectations, CD69+, CXCR3+, CD103− Trm cells failed to protect against a lethal pulmonary fungal infection. Surprisingly, systemic vaccination induced a population of tetramer+ CD4+ T cells enriched within the pulmonary vasculature, and expressing CXCR3 and CX3CR1, that migrated to the lung tissue upon challenge and efficiently protected mice against infection. Mucosal vaccine priming of Trm may not reliably protect against mucosal pathogens.

Reference:  Dobson, H.E., Dias, L.D.S., Kohn, E.M. et al. Antigen discovery unveils resident memory and migratory cell roles in antifungal resistance. Mucosal Immunol (2020). Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse IFN-γ (Clone: XMG1.2) and anti-mouse IL-17A (Clone: 17F3) in this research study.

 


Inducing Tumor Suppressive Microenvironments through Genome Edited CD47−/− Syngeneic Cell Vaccination

Inducing Tumor Suppressive Microenvironments through Genome Edited CD47−/− Syngeneic Cell Vaccination

 

 

 

 

Authors: Subhadra Jayaraman Rukmini, Huanjing Bi, Puloma Sen, Benjamin Everhart, Sha Jin & Kaiming Ye

 

 

Abstract

Tumors can escape from the immune system by overexpressing CD47 and other checkpoint blockades. CD47 is expressed ubiquitously by all cells in the body, posing an obstacle for CD47 blocking treatments due to their systemic toxicity. We performed a study to determine how the tumor microenvironment changes after vaccination with genome edited CD47−/− syngeneic tumor cells. We discovered that inactivated CD47-depleted mouse melanoma cells can protect mice from melanoma. Our animal study indicated that 33% of vaccinated mice remained tumor-free, and 100% of mice had 5-fold reduced growth rates. The characterization of immunomodulatory effects of the vaccine revealed a highly anti-tumorigenic and homogenous microenvironment after vaccination. We observed consistently that in the tumors that failed to respond to vaccines, there were reduced natural killer cells, elevated regulatory T cells, M2-type macrophages, and high PD-L1 expression in these cells. These observations suggested that the tumor microenvironments became more suppressive to tumor growth after vaccination, suggesting a potential new immunotherapy for solid tumors.

Reference:  Jayaraman Rukmini, S., Bi, H., Sen, P. et al. Inducing Tumor Suppressive Microenvironments through Genome Edited CD47−/− Syngeneic Cell Vaccination. Sci Rep 9, 20057 (2019) doi:10.1038/s41598-019-56370-6. Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse/human TYRP1/TRP1 (gp75) (Clone: TA99) in this research study.

 


CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome

CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome

 

 

 

 

Authors: Catharina C. Gross, Céline Meyer, Urvashi Bhatia, Lidia Yshii, Ilka Kleffner, Jan Bauer, Anna R. Tröscher, Andreas Schulte-Mecklenbeck, Sebastian Herich, Tilman Schneider-Hohendorf, Henrike Plate, Tanja Kuhlmann, Markus Schwaninger, Wolfgang Brück, Marc Pawlitzki, David-Axel Laplaud, Delphine Loussouarn, John Parratt, Michael Barnett, Michael E. Buckland, Todd A. Hardy, Stephen W. Reddel, Marius Ringelstein, Jan Dörr, Brigitte Wildemann, Markus Kraemer, Hans Lassmann, Romana Höftberger, Eduardo Beltrán, Klaus Dornmair, Nicholas Schwab, Luisa Klotz, Sven G. Meuth, Guillaume Martin-Blondel, Heinz Wiendl & Roland Liblau

 

 

Abstract

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8+ T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8+ T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities.

Reference:  Gross, C.C., Meyer, C., Bhatia, U. et al. CD8+ T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nat Commun 10, 5779 (2019) doi:10.1038/s41467-019-13593-5. Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse/human VLA-4 (CD49d) in this research study.

 


Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs

Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs

 

 

 

Authors: Buqing Sai, Yafei Dai, Songqing Fan, Fan Wang, Lujuan Wang, Zheng Li, Jingqun Tang, Li Wang, Xina Zhang, Leliang Zheng, Fei Chen, Guiyuan Li & Juanjuan Xiang

 

 

Abstract

Bone marrow mesenchymal stem cells (BMSCs) are multipotent stromal cells that can differentiate into a variety of cell types. BMSCs are chemotactically guided towards the cancer cells and contribute to the formation of a cancer microenvironment. The homing of BMSCs was affected by various factors. Disseminated tumour cells (DTCs) in distant organs, especially in the bone marrow, are the source of cancer metastasis and cancer relapse. DTC survival is also determined by the microenvironment. Here we aim to elucidate how cancer-educated BMSCs promote the survival of cancer cells at primary tumour sites and distant sites. We highlight the dynamic change by identifying different gene expression signatures in intratumoral BMSCs and in BMSCs that move back in the bone marrow. Intratumoral BMSCs acquire high mobility and displayed immunosuppressive effects. Intratumoral BMSCs that ultimately home to the bone marrow exhibit a strong immunosuppressive function. Cancer-educated BMSCs promote the survival of lung cancer cells via expansion of MDSCs in bone marrow, primary tumour sites and metastatic sites. These Ly6G+ MDSCs suppress proliferation of T cells. CXCL5, nitric oxide and GM-CSF produced by cancer-educated BMSCs contribute to the formation of malignant microenvironments. Treatment with CXCL5 antibody, the iNOS inhibitor 1400w and GM-CSF antibody reduced MDSC expansion in the bone marrow, primary tumour sites and metastatic sites, and promoted the efficiency of PD-L1 antibody. Our study reveals that cancer-educated BMSCs are the component of the niche for primary lung cancer cells and DTCs, and that they can be the target for immunotherapy.

Reference:  Sai, B., Dai, Y., Fan, S. et al. Cancer-educated mesenchymal stem cells promote the survival of cancer cells at primary and distant metastatic sites via the expansion of bone marrow-derived-PMN-MDSCs. Cell Death Dis 10, 941 (2019) doi:10.1038/s41419-019-2149-1. Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-L1 (B7-H1) in this research study.

 


PAK4 inhibition improves PD-1 blockade immunotherapy

PAK4 inhibition improves PD-1 blockade immunotherapy

 

 

 

 

 

 

Authors: Gabriel Abril-Rodriguez, Davis Y. Torrejon, Wei Liu, Jesse M. Zaretsky, Theodore S. Nowicki, Jennifer Tsoi, Cristina Puig-Saus, Ignacio Baselga-Carretero, Egmidio Medina, Michael J. Quist, Alejandro J. Garcia, William Senapedis, Erkan Baloglu, Anusha Kalbasi, Gardenia Cheung-Lau, Beata Berent-Maoz, Begoña Comin-Anduix, Siwen Hu-Lieskovan, Cun-Yu Wang, Catherine S. Grasso & Antoni Ribas

 

 

Abstract

Lack of tumor infiltration by immune cells is the main mechanism of primary resistance to programmed cell death protein 1 (PD-1) blockade therapies for cancer. It has been postulated that cancer cell-intrinsic mechanisms may actively exclude T cells from tumors, suggesting that the finding of actionable molecules that could be inhibited to increase T cell infiltration may synergize with checkpoint inhibitor immunotherapy. Here, we show that p21-activated kinase 4 (PAK4) is enriched in non-responding tumor biopsies with low T cell and dendritic cell infiltration. In mouse models, genetic deletion of PAK4 increased T cell infiltration and reversed resistance to PD-1 blockade in a CD8 T cell-dependent manner. Furthermore, combination of anti-PD-1 with the PAK4 inhibitor KPT-9274 improved anti-tumor response compared with anti-PD-1 alone. Therefore, high PAK4 expression is correlated with low T cell and dendritic cell infiltration and a lack of response to PD-1 blockade, which could be reversed with PAK4 inhibition.

Reference:  Abril-Rodriguez, G., Torrejon, D.Y., Liu, W. et al. PAK4 inhibition improves PD-1 blockade immunotherapy. Nat Cancer (2019) doi:10.1038/s43018-019-0003-0. Retrieved from https://www.nature.com/

Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-1 (CD279) and anti-mouse CD8α in this research study.

 


TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis

Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection

 

 

 

 

 

Authors: Macal M1, Jo Y1, Dallari S1, Chang AY, Dai J, Swaminathan S, Wehrens EJ, Fitzgerald-Bocarsly P, Zúñiga EI

 

 

Abstract

Although characterization of T cell exhaustion has unlocked powerful immunotherapies, the mechanisms sustaining adaptations of short-lived innate cells to chronic inflammatory settings remain unknown. During murine chronic viral infection, we found that concerted events in bone marrow and spleen mediated by type I interferon (IFN-I) and Toll-like receptor 7 (TLR7) maintained a pool of functionally exhausted plasmacytoid dendritic cells (pDCs). In the bone marrow, IFN-I compromised the number and the developmental capacity of pDC progenitors, which generated dysfunctional pDCs. Concurrently, exhausted pDCs in the periphery were maintained by self-renewal via IFN-I- and TLR7-induced proliferation of CD4- subsets. On the other hand, pDC functional loss was mediated by TLR7, leading to compromised IFN-I production and resistance to secondary infection. These findings unveil the mechanisms sustaining a self-perpetuating pool of functionally exhausted pDCs and provide a framework for deciphering long-term exhaustion of other short-lived innate cells during chronic inflammation.

Reference:  Immunity. Author manuscript; available in PMC 2019 Apr 17.
Published in final edited form as: Immunity. 2018 Apr 17; 48(4): 730–744.e5. doi: 10.1016/j.immuni.2018.03.020. Retrieved from https://www.sciencedirect.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse IFNAR-1 and mouse IgG1 isotype control in this research study.

 


TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis

TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis

 

Authors: Lele Zhu, Yanchuan Li, Xiaoping Xie, Xiaofei Zhou, Meidi Gu, Zuliang Jie, Chun-Jung Ko, Tianxiao Gao, Blanca E. Hernandez, Xuhong Cheng & Shao-Cong Sun

 

 

Abstract

TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor—TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1–TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1–TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ–TBKBP1–TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression.

Reference:  Zhu, L., Li, Y., Xie, X. et al. TBKBP1 and TBK1 form a growth factor signalling axis mediating immunosuppression and tumourigenesis. Nat Cell Biol (2019) doi:10.1038/s41556-019-0429-8. Retrieved from https://www.nature.com/ncb/

Product Highlights:

The authors used Bio X Cell’s anti-mouse CD3ε, polyclonal Armenian hamster IgG, anti-mouse CTLA-4 (CD152), and polyclonal Syrian hamster IgG in this research study.

 


Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors.

Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors

 

 

 

Authors: Ponzetta, Carriero, Carnevale, Barbagallo, Molgora, Perucchini, Magrini, Gianni, Kunderfranco, Polentarutti, Pasqualini, Di Marco, Supino, Peano, Cananzi, Colombo, Pilotti, Alomar, Bonavita, Galdiero, Garlanda, & Mantovani, Jaillon

 

 

Abstract

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αβ T cells (UTCαβ). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαβ associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαβ polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.

Reference:  Ponzetta, C. et al. “Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors” (11 July 2019). Cell 178, 346–360 (2019). Retrieved from https://www.cell.com

Product Highlights:

The authors used Bio X Cell’s anti-mouse Ly6G, anti-mouse IFNγ, anti-mouse IL-12 p75, and anti-mouse CSF1R (CD115) depleting antibodies in this research study.

 


A rationale for surgical debulking to improve anti-PD1 therapy outcome in non small cell lung cancer

 

 

 

 

Authors: Florian Guisier, Stephanie Cousse, Mathilde Jeanvoine, Luc Thiberville, & Mathieu Salaun

 

 

 

Abstract

Anti-PD1 immunotherapy has emerged as a gold-standard treatment for first- or second-line treatment of stage IV NSCLC, with response rates ranging from 10 to 60%. Strategies to improve the disease control rate are needed. Several reports suggested that debulking surgery enhances anti-tumor immunity. We aimed at examining tumor burden as a predictive factor of anti-PD1 treatment efficacy and to evaluate the role of cytoreductive surgery in anti-PD1 treated NSCLC. Immunocompetent DBA/2 mice engrafted with various amount of allogeneic lung squamous cancer KLN-205 cells were treated with anti-PD1 monoclonal antibody. Mice engrafted with two tumors also underwent a debulking surgery or a sham procedure. Tumor volume was monitored to assess treatment efficacy. Tumor infiltrating lymphocytes were assessed by flow cytometry. In a retrospective study of 48 stage IV NSCLC patients treated with Nivolumab who underwent a 18-FDG PETscan before treatment onset, the prognostic role of metabolic tumor volume was analyzed. Anti-PD1 treatment effect was greater in mice bearing smaller tumors. Treatment with higher doses of anti-PD1 antibody did not improve the outcome, independently of the size of the tumor. In mice bearing 2 tumors, excision of 1 tumor improved the anti-PD1 treatment effect on the remaining tumor. In 48 NSCLC patients receiving anti-PD1 treatment, high metabolic tumor volume was associated with poor overall survival and the absence of clinical benefit. Treg infiltration, but not effector T cells, was positively correlated to tumor volume. Taken together, our results suggest that tumor volume is a predictive factor of anti-PD1 efficacy in NSCLC. Additionally, an experimental murine model suggests that tumor debulking may improve control of residual tumor.

Reference:  Guisier, F. et al. “A rationale for surgical debulking to improve anti-PD1 therapy outcome in non small cell lung cancer” (15 November 2019). Scientific Reports volume 9, Article number: 16902 (2019). Retrieved from https://www.nature.com/articles/s41598-019-53434-5

Product Highlights:

The authors used Bio X Cell’s anti-mouse PD-1 (CD279)(Clone: J43) in this research study.

 


 

A novel mouse model for septic arthritis induced by Pseudomonas aeruginosa

 

 

 

 

 

Authors: Tao Jin, Majd Mohammad, Zhicheng Hu, Ying Fei, Edward R. B. Moore, Rille Pullerits & Abukar Ali

 

 

 

Abstract

Septic arthritis is one of the most aggressive joint diseases. Although caused predominantly by S. aureus, Gram-negative bacteria, Pseudomonas aeruginosa among them, account for a significant percentage of the causal agents of septic arthritis. However, septic arthritis caused by P. aeruginosa has not been studied thus far, due to lack of an animal model. NMRI mice were inoculated with different doses of P. aeruginosa. The clinical course of septic arthritis and radiological changes of joints were examined. Furthermore, the host molecular and cellular mechanisms involved in P. aeruginosa-induced septic arthritis were investigated. Inoculation of mice with P. aeruginosa caused septic arthritis in a dose-dependent manner. Neutrophil depletion led to higher mortality and more severe joint destruction (p < 0.01). In contrast, monocyte depletion resulted in higher mortality (p < 0.05) but similar arthritis severity compared to controls. Mice depleted of CD4+ T-cells inoculated with P. aeruginosa displayed less severe bone damage (p < 0.05). For the first time, a mouse model for P. aeruginosa septic arthritis is presented. Our data demonstrate that neutrophils play a protective role in P. aeruginosa septic arthritis. Monocytes/macrophages, on the other hand, are only essential in preventing P. aeruginosa-induced mortality. Finally, CD4+ T-cells are pathogenic in P. aeruginosa septic arthritis.

Reference:  Jin, T. et al. “A novel mouse model for septic arthritis induced by Pseudomonas aeruginosa” (14 November 2019). Scientific Reports volume 9, Article number: 16868 (2019). Retrieved from https://www.nature.com/articles/s41598-019-53434-5

Product Highlights:

The authors used Bio X Cell’s anti-mouse Ly6G (clone 1A8) antibody for neutrophil depletion, anti-mouse CD4 (clone: GK1.5) antibody for CD4 T cell depletion, and anti-mouse anti-mouse CD8α (clone 2.43) antibody for CD8 T cell depletion.