B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas

B 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. •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⁺ Tcells to SCCs via CCR5. Affara etal. show that human squamous cell carcinomas (SCCs) associated with high-risk HPV are infiltrated by Ig-producing B cells. Therapeutic B cell depletion in mice bearing preexisting SCCs reprograms macrophages to recruit CD8⁺ Tcells to SCCs via CCR5 and improves chemotherapeutic efficacy.