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 Khan, Seung-Uon Shin, Hyun Mi Cho, Ahmed Al Bayati, Augustin Pimentel, Joseph D Rosenblatt

Research output: Contribution to journalArticle

36 Citations (Scopus)

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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B-Lymphocytes
Breast Neoplasms
Neoplasms
T-Lymphocytes
Natural Killer Cells
Cell Proliferation
Interleukin-15
Coculture Techniques
Cytokines
Phenotype
Antibodies

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Mammary-tumor-educated b cells acquire lap/tgf-β and pd-l1 expression and suppress antitumor immune responses. / Zhang, Yu; Morgan, Richard; Chen, Chuan; Cai, Yancheng; Clark, Emily; Khan, Wasif; Shin, Seung-Uon; Cho, Hyun Mi; Bayati, Ahmed Al; Pimentel, Augustin; Rosenblatt, Joseph D.

In: International Immunology, Vol. 28, No. 9, 01.09.2016, p. 423-433.

Research output: Contribution to journalArticle

Zhang, Yu ; Morgan, Richard ; Chen, Chuan ; Cai, Yancheng ; Clark, Emily ; Khan, Wasif ; Shin, Seung-Uon ; Cho, Hyun Mi ; Bayati, Ahmed Al ; Pimentel, Augustin ; Rosenblatt, Joseph D. / Mammary-tumor-educated b cells acquire lap/tgf-β and pd-l1 expression and suppress antitumor immune responses. In: International Immunology. 2016 ; Vol. 28, No. 9. pp. 423-433.
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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.",
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AU - Morgan, Richard

AU - Chen, Chuan

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AU - Clark, Emily

AU - Khan, Wasif

AU - Shin, Seung-Uon

AU - Cho, Hyun Mi

AU - Bayati, Ahmed Al

AU - Pimentel, Augustin

AU - Rosenblatt, Joseph D

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AB - 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.

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