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 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

Fingerprint

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 Noor; 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

@article{cf11dc31fe584d86aae7738e53e7f75a,
title = "Mammary-tumor-educated b cells acquire lap/tgf-β and pd-l1 expression and suppress antitumor immune responses",
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.",
keywords = "Anti-tumor response, B regulatory cells, PD-L1, TGF-β",
author = "Yu Zhang and Richard Morgan and Chuan Chen and Yancheng Cai and Emily Clark and Khan, {Wasif Noor} and Shin, {Seung Uon} and Cho, {Hyun Mi} and Bayati, {Ahmed Al} and Augustin Pimentel and Rosenblatt, {Joseph D.}",
year = "2016",
month = "9",
day = "1",
doi = "10.1093/intimm/dxw007",
language = "English (US)",
volume = "28",
pages = "423--433",
journal = "International Immunology",
issn = "0953-8178",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - Mammary-tumor-educated b cells acquire lap/tgf-β and pd-l1 expression and suppress antitumor immune responses

AU - Zhang, Yu

AU - Morgan, Richard

AU - Chen, Chuan

AU - Cai, Yancheng

AU - Clark, Emily

AU - Khan, Wasif Noor

AU - Shin, Seung Uon

AU - Cho, Hyun Mi

AU - Bayati, Ahmed Al

AU - Pimentel, Augustin

AU - Rosenblatt, Joseph D.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

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.

KW - Anti-tumor response

KW - B regulatory cells

KW - PD-L1

KW - TGF-β

UR - http://www.scopus.com/inward/record.url?scp=84987970956&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84987970956&partnerID=8YFLogxK

U2 - 10.1093/intimm/dxw007

DO - 10.1093/intimm/dxw007

M3 - Article

C2 - 26895637

AN - SCOPUS:84987970956

VL - 28

SP - 423

EP - 433

JO - International Immunology

JF - International Immunology

SN - 0953-8178

IS - 9

ER -