Mammary-tumor-educated b cells acquire lap/tgf-β and pd-l1 expression and suppress antitumor immune responses

Yu Zhang, Richard Morgan, Chuan Chen, Yancheng Cai, Emily Clark, Wasif Noor Khan, Seung Uon Shin, Hyun Mi Cho, Ahmed Al Bayati, Augustin Pimentel, Joseph D. Rosenblatt

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

B lymphocytes play a role in inhibiting the immune response against certain tumors, but the underlying mechanisms are poorly understood. EMT-6 mammary tumors grow well in wild-type (WT) mice but show reduced growth in B-cell-deficient μ-/- BALB/c mice (BCDM). WT mice demonstrate extensive B-cell infiltration into the tumor bed, reduced CD8+ T cell and CD49+ NK cell infiltration, and markedly reduced cytolytic T-cell response relative to BCDM. Expression of LAP/TGF-β1, CD80, CD86 and PD-L1 is significantly increased in tumor-infiltrating B cells (TIL-B) relative to splenic B cells. LAP/TGF-β1 expression on TIL-B progressively increased from 5.4 ± 1.7% on day 8 to 43.1 ± 6.1% by day 21 post tumor implantation. Co-culture of EMT-6 tumor cells with Naive-B cells ex vivo generated B cells (EMT6-B) with a similar immunophenotype to TIL-B. Purified TIL-B, or in-vitro-generated EMT6-B suppressed CD4+, CD8+ and CD4+CD25- T-cell proliferation, and Th1 cytokine secretion, and also suppressed purified NK-cell proliferation in response to IL-15, compared to naive splenic B cells. Acquired B regulatory function required direct tumor cell: B-cell contact, and was partially reversed by antibody to TGF-β or PD-L1, leading to tumor rejection in vivo. B-cell acquisition of a suppressive phenotype following tumor infiltration may result in profound inhibition of T-cell antitumor responses.

Original languageEnglish (US)
Pages (from-to)423-433
Number of pages11
JournalInternational Immunology
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2016

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Keywords

  • Anti-tumor response
  • B regulatory cells
  • PD-L1
  • TGF-β

ASJC Scopus subject areas

  • Immunology

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