B Cells Regulate Macrophage Phenotype and Response to Chemotherapy in Squamous Carcinomas

• Human SCCs associated with high-risk HPV are infiltrated by Ig-producing B cells
• B cell depletion or FcγR signaling inhibition impedes SCC neoplastic progression
• Therapeutic B cell depletion enhances response of established SCCs to chemotherapy
• B cell depletion reprograms macrophages to recruit CD8+ T cells to SCCs via CCR5

SummaryB cells foster squamous cell carcinoma (SCC) development through deposition of immunoglobulin-containing immune complexes in premalignant tissue and Fcγ receptor-dependent activation of myeloid cells. Because human SCCs of the vulva and head and neck exhibited hallmarks of B cell infiltration, we examined B cell-deficient mice and found reduced support for SCC growth. Although ineffective as a single agent, treatment of mice bearing preexisting SCCs with B cell-depleting αCD20 monoclonal antibodies improved response to platinum- and Taxol-based chemotherapy. Improved chemoresponsiveness was dependent on altered chemokine expression by macrophages that promoted tumor infiltration of activated CD8+ lymphocytes via CCR5-dependent mechanisms. These data reveal that B cells, and the downstream myeloid-based pathways they regulate, represent tractable targets for anticancer therapy in select tumors.