Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors.
Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors.
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DOI：
10.1080/2162402x.2017.1421891
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Hartman ZC
中科院分区：
文献类型：
--
作者：
Crosby EJ;Wei J;Yang XY;Lei G;Wang T;Liu CX;Agarwal P;Korman AJ;Morse MA;Gouin K;Knott SRV;Lyerly HK;Hartman ZC
三阴性乳腺癌（TNBC）是一种侵袭性和分子多样性的乳腺癌亚型，其典型特征是p53突变（约80%）、免疫基因特征和新抗原表达升高，以及肿瘤浸润淋巴细胞（TILs）的存在。由于这些因素被假设为使用免疫检查点阻断（ICB）抗体的强大免疫学先决条件，测试单一ICB的多项临床试验已进入III期，早期适应症显示抗pd1和抗pdl1 ICB的异质性反应率<20%。虽然有希望，但这些适度的缓解率强调了机制研究的必要性，以了解不同的ICBs如何起作用，它们的组合如何影响功能和疗效，以及哪些免疫参数预测TNBC中不同ICBs方案的疗效。为了解决这些问题，我们在多种TNBC模型中测试了抗pd1和抗ctla4，发现它们的联合治疗大大提高了单独治疗的疗效。我们证明，这种功效是由于抗ctla4驱动的单个独特的t细胞受体（TCR）库的扩增，其功能通过肿瘤内Treg抑制和抗pd1阻断肿瘤表达的PDL1而增强。值得注意的是，无论肿瘤细胞是否表达非自身抗原（卵清蛋白），还是在测序之前转移肿瘤特异性转基因t细胞，都可以观察到TCR库的个性。然而，应答性与肿瘤特异性t细胞和b细胞应答的系统性测量密切相关，这与TCR扩增的系统性评估一起，可能成为未来使用抗pd1 /抗ctla4 ICB治疗TNBC临床试验中最有用的临床应答性预测指标。
Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (∼80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor-specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB.