In addition to endogenous genetic alterations, malignant progression and therapeutic responses are strongly modulated by the innate and adaptive immune systems. Androgen depletion and malignant progression induce lymphocyte recruitment into prostate cancer (PC). Recruited B cells produce lymphotoxin (LT), an inflammatory cytokine that stimulates expansion of androgen-deprived PC progenitors. Recruited B cells also control the response of PC to the immunogenic chemotherapeutic agent oxaliplatin, which at a low, non-myelosuppressive dose, induces immunogenic cell death that promotes generation of tumor-directed cytotoxic T cells (CTL). In three different mouse PC models the resulting tumors do not respond to low dose oxaliplatin unless grown in B cell-deficient hosts. The B lymphocytes responsible for immunosuppression are plasma cells that express IgA, IL-10 and PD-L1, but not LT, whose appearance depends on TGFβ-receptor (TGFβR) signaling. Elimination of these cells, which also infiltrate human therapy-resistant PC, facilitates CTL-dependent eradication of oxaliplatin-treated tumors.
Ammirante, M., Kuraishy, A.I., Shalapour, S., Strasner, A., Ramirez-Sanchez, C., Zhang, W., Shabaik, A., and Karin, M. (2013). An IKKalpha-E2F1-BMI1 cascade activated by infiltrating B cells controls prostate regeneration and tumor recurrence. Genes Dev 27:1435-1440.
Ammirante, M., Luo, J.L., Grivennikov, S., Nedospasov, S., and Karin, M. (2010). B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464:302-305.
Grivennikov, S.I., Greten, F.R., and Karin, M. (2010). Immunity, inflammation, and cancer. Cell 140:883-899.
Citation Format: Michael Karin. The intersection of inflammation, immunity, and cancer: From basic biology to translational research. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA02.
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