B Cells Can Suppress Chemotherapy-Induced Immunogenic Cell Death

Some chemotherapeutic agents, such as oxaliplatin, a platinum-based compound that is being investigated as a potential prostate cancer therapy, stimulate immunogenic cell death and activate cytotoxic T lymphocytes (CTL). Shalapour and colleagues found that tumors arising in independent mouse models of prostate cancer ultimately became resistant to oxaliplatin in association with increased levels of tumor-infiltrating IgA⁺ plasmocytic B cells. A large subset of the tumor-infiltrating IgA⁺ B-cell population expressed IL10 and PD-L1, which have both been implicated in T-cell anergy and exhaustion. Oxaliplatin resistance could be overcome and CTL-dependent tumor regression could be induced by genetic or pharmacologic B-cell depletion or by specifically blocking the generation of the immunosuppressive IgA⁺ plasmocytes through inhibition of TGFβR2 signaling. B-cell depletion or inhibition of TGFβR2-dependent IgA⁺ plasmocyte generation also enhanced the effectiveness of adoptive T-cell transfer in combination with oxaliplatin. Notably, a similar IgA⁺ B-cell population could be detected in human prostate cancer samples, with a higher level of IgA⁺ plasmocytes and lower frequency of CTLs in treatment-resistant and metastatic tumor samples compared with early tumors, suggesting that an immunosuppressive B-cell population may also promote tumor progression and immune evasion in human prostate cancer and possibly represent an attractive therapeutic target. These findings also raise the possibility that inhibition or elimination of tumor-infiltrating IgA⁺ plasmocytes may increase antitumor immune responses and subsequently augment the activity of immunogenic chemotherapy alone or in combination with immunotherapy, especially in diseases such as prostate cancer that do not respond to single immune checkpoint inhibitor therapies.

Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, et al. Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature 2015;521:94–8.

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