Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Tumor antigens activate CD8(+) cytotoxic T lymphocytes (CTLs), but established tumors create immune tolerance.
• Therapies overcoming tolerance activate tumor-directed CTLs, showing efficacy in some human cancers.
• Chemotherapy can stimulate anti-cancer immune responses via immunogenic cell death.

Purpose of the Study:

• Investigate B cell involvement in chemotherapy resistance in castrate-resistant prostate cancer (CRPC).
• Determine the role of B cells in modulating the response to oxaliplatin, an immunogenic chemotherapeutic agent.
• Identify specific B cell populations contributing to immunosuppression and therapy resistance.

Main Methods:

• Utilized three mouse prostate cancer models.
• Examined the effects of B cell depletion (genetic or pharmacologic) on oxaliplatin treatment response.
• Characterized immunosuppressive B cells by their surface markers and cytokine production (IgA, IL-10, PD-L1).

Main Results:

• Mouse prostate cancer models were refractory to oxaliplatin unless B cells were depleted.
• Low-dose oxaliplatin promoted tumor-directed CTL activation by inducing immunogenic cell death, but this was inhibited by B cells.
• Specific immunosuppressive B cells expressing IgA, IL-10, and PD-L1, dependent on TGFβ receptor signaling, were identified as crucial for resistance.
• Elimination of these B cells permitted CTL-dependent tumor eradication in oxaliplatin-treated mice.

Conclusions:

• B cells, particularly IgA+, IL-10+, PD-L1+ plasmocytes, are critical mediators of chemotherapy resistance in prostate cancer.
• Targeting these immunosuppressive B cells can restore sensitivity to oxaliplatin and enhance CTL-mediated tumor eradication.
• These findings highlight a novel therapeutic strategy for overcoming resistance in aggressive prostate cancer.