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Posted on: November 27, 2019
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
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/
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
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
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
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
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
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
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.