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Mammary-tumor-educated B cells acquire LAP/TGF-? and PD-L1 expression and
suppress anti-tumor immune responses
#MMPMID26895637
Zhang Y
; Morgan R
; Chen C
; Cai Y
; Clark E
; Khan WN
; Shin SU
; Cho HM
; Al Bayati A
; Pimentel A
; Rosenblatt JD
Int Immunol
2016[Sep]; 28
(9
): 423-33
PMID26895637
show ga
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
?(-/-) 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-?1, CD80, CD86 and PD-L1 is significantly increased in tumor-infiltrating
B cells (TIL-B) relative to splenic B cells. LAP/TGF-?1 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-? 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 anti-tumor responses.
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