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Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer.

ABSTRACT: Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment with immune checkpoint blockade (ICB) antibodies. We also observed that high MRTF signaling in human melanoma is associated with ICB efficacy in patients. Using biophysical and functional assays, we showed that MRTF overexpression rigidified the filamentous actin cytoskeleton and that this mechanical change rendered mouse and human cancer cells more vulnerable to cytotoxic T lymphocytes and natural killer cells. Collectively, these results suggest that immunosurveillance has a mechanical dimension, which we call mechanosurveillance, that is particularly relevant for the targeting of metastatic disease.

SUBMITTER: Tello-Lafoz M

PROVIDER: S-EPMC8119359 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer.

Tello-Lafoz Maria M Srpan Katja K Sanchez Elisa E EE Hu Jing J Remsik Jan J Romin Yevgeniy Y Calò Annalisa A Hoen Douglas D Bhanot Umeshkumar U Morris Luc L Boire Adrienne A Hsu Katharine C KC Massagué Joan J Huse Morgan M Er Ekrem Emrah EE

Immunity 20210322 5

Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment ...[more]

PMID: 33756102

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Project description:Background: Despite current therapeutic treatments including surgery, chemotherapy, radiotherapy and recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered a dual function of a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the lung cancer immune response. Methods: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterize by flow cytometry. Results In this study, we first show that QAPHA can inhibit HDAC6, leading to upregulation of HSP90, cytochrome C and caspases, found by proteomic analysis. We also confirm that QAPHA induces immunogenic cell death (ICD) by upregulating HMGB1 in vitro and demonstrated its effectiveness as a vaccine in vivo. Remarkably, even at a low concentration (0.5mg/kg), QAPHA achieved complete tumor regression in approximately 60% of intratumorally treated mice, establishing a long-lasting anticancer immune response. Moreover, QAPHA treatment promoted infiltration of neutrophils in the treated mice, reflecting inflammatory cell death promoted. Very interestingly, we show that QAPHA is also able to upregulate MHC-II expression on TC-1 tumor cells in vitro and in vivo. This process participates to the recruitment of CD4+ NKG2D+ CRTAM+ Perforin+ T cells in tumor infiltrate, defined as cytotoxic CD4+ T cells (CD4+ CTL). Finally, we show that tumor regression is strongly correlated to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. Conclusion Collectively, our findings shed light on the discovery of a new multi-target inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate to enhance a specific CD4+ cytotoxic T cell-mediated anti-tumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising therapeutic agent for cancer treatment.

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Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer.

Publications

Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer.

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