B-cell depletion with anti-CD20 mAb enhances chemotherapy response in mouse models of SCC.

  • Major finding: B-cell depletion with anti-CD20 mAb enhances chemotherapy response in mouse models of SCC.

  • Mechanism: Anti-CD20 therapy reprograms macrophages to augment CCR5-dependent CD8+ T-cell recruitment.

  • Impact: Inhibition of humoral immunity may improve antitumor immune responses in various solid tumors.

B cells have been revealed to promote solid tumorigenesis via their production of immunoglobulins and stimulation of proangiogenic, tissue-remodeling, and prosurvival signaling in myeloid cells infiltrating squamous cell carcinomas (SCC), suggesting that inhibition of humoral immunity may be therapeutically beneficial. To test this hypothesis, Affara and colleagues used mice that develop human papillomavirus (HPV)–driven SCC as a model of tumor progression recapitulating aspects of human vulva and head and neck SCC, which exhibited increased CD20 and immunoglobulin expression and enhanced B-cell infiltration. Depletion of B cells with anti-CD20 mAb or selective inhibition of spleen tyrosine kinase with fostamatinib diminished angiogenesis and keratinocyte proliferation and prevented neoplastic progression of premalignant hyperplastic lesions. In addition, although anti-CD20 mAb monotherapy was not sufficient to repress the growth of established SCCs, combined treatment with platinum-based or paclitaxel chemotherapy significantly slowed preexistent SCC growth, indicating that inhibition of B-cell signaling improves the chemoresponsiveness of SCCs. Decreased tumor growth was dependent on increased expression of angiostatic chemokines and chemokines that promote T-cell recruitment, including chemokine (C-C motif) ligand 5 (CCL5), emanating from macrophages, suggesting that CD20 blockade enables macrophages in neoplastic tissue to reprogram to instead favor a TH1-like phenotype that facilitates antitumor immune responses. Consistent with this idea, dual anti-CD20 mAb and paclitaxel treatment resulted in enhanced infiltration of cytotoxic CD8+ T cells in tumors, which was mediated by CCL5 signaling through its receptor CCR5 on T cells and was required for sensitization of established SCCs to paclitaxel. These results demonstrate that B cell–regulated macrophage signaling impairs the response of SCCs to chemotherapy in part by suppressing cytotoxic T-cell infiltration and supports the contention that targeted inhibition of protumor B cells may enhance the efficacy of chemotherapeutic agents in SCC and other solid tumors.

Affara NI, Ruffell B, Medler TR, Gunderson AJ, Johansson M, Bornstein S, et al. B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 2014;25:809–21.