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

Nesrine I. Affara, Brian Ruffell, Terry R. Medler, Andrew J. Gunderson, Magnus Johansson, Sophia Bornstein, Emily Bergsland, Martin Steinhoff, Yijin Li, Qian Gong, Yan Ma, Jane F. Wiesen, Melissa H. Wong, Molly Kulesz-Martin, Bryan Irving, Lisa M. Coussens

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)809-821
Number of pages13
JournalCancer Cell
Volume25
Issue number6
DOIs
StatePublished - Jun 16 2014

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Affara, N. I., Ruffell, B., Medler, T. R., Gunderson, A. J., Johansson, M., Bornstein, S., Bergsland, E., Steinhoff, M., Li, Y., Gong, Q., Ma, Y., Wiesen, J. F., Wong, M. H., Kulesz-Martin, M., Irving, B., & Coussens, L. M. (2014). B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell, 25(6), 809-821. https://doi.org/10.1016/j.ccr.2014.04.026