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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/

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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/

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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.

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