Mammary-tumor-educated B cells acquire LAP/TGF-β and PD-L1 expression and suppress antitumor immune responses
Mammary-tumor-educated B cells acquire LAP/TGF-β and PD-L1 expression and suppress antitumor immune responses
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DOI：
10.1093/intimm/dxw007
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发表时间：
2016-09-01
影响因子：
4.4
通讯作者：
Rosenblatt, Joseph D.
中科院分区：
文献类型：
--
作者：
Zhang, Yu;Morgan, Richard;Rosenblatt, Joseph D.
B淋巴细胞在抑制针对某些肿瘤的免疫应答中发挥作用，但其潜在机制知之甚少。EMT-6乳腺肿瘤在野生型（WT）小鼠中生长良好，但在B细胞缺陷型mu（-/-）BALB/c小鼠（BCDM）中生长减少。WT小鼠表现出广泛的B细胞浸润到肿瘤床中，减少的CD 8 + T细胞和CD 49（+）NK细胞浸润，以及相对于BCDM显著降低的细胞溶解性T细胞应答。相对于脾B细胞，肿瘤浸润性B细胞（TIL-B B）中的CD 4/TGF-β 1、CD 80、CD 86和PD-L1的表达显著增加。肿瘤植入后第8天，TIL-B上的TGF-β 1/TGF-β 1表达从5.4 +/- 1.7%逐渐增加至43.1 +/- 6.1%。EMT-6肿瘤细胞与初始-B细胞的离体共培养产生具有与TIL-B相似的免疫表型的B细胞（EMT 6-B）。纯化的TIL-B或体外产生的EMT 6-B抑制了CD 4（+）、CD 8+和CD 4（+）CD 25-T细胞增殖，以及Th 1细胞因子分泌，并且与初始脾B细胞相比，还抑制了响应于IL-15的纯化NK细胞增殖。获得性B调节功能需要直接的肿瘤细胞：B细胞接触，并且被TGF-β或PD-L1抗体部分逆转，导致体内肿瘤排斥。肿瘤浸润后B细胞获得抑制性表型可能导致T细胞抗肿瘤反应的严重抑制。
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 mu(-/-) 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-beta 1, CD80, CD86 and PD-L1 is significantly increased in tumor-infiltrating B cells (TIL-B) relative to splenic B cells. LAP/TGF-beta 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-beta 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.