Tumor cell SYK expression modulates the tumor immune microenvironment composition in human cancer via TNF-α dependent signaling.
Tumor cell SYK expression modulates the tumor immune microenvironment composition in human cancer via TNF-α dependent signaling.
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肿瘤细胞SYK的表达通过肿瘤坏死因子-α依赖的信号调节肿瘤免疫微环境的组成。
DOI：
10.1136/jitc-2022-005113
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发表时间：
2022-07
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
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作者：
SYK在癌细胞中的表达与促瘤和抑瘤作用有关。尽管SYK被提出作为抗癌治疗靶点，但它在调节局部适应性抗肿瘤免疫反应中的可能作用仍不确定。通过对人原发性肿瘤和体外模型的详细分析，我们揭示了SYK蛋白在人实体癌中的免疫调节作用。我们对来自两个独立队列的808例原发性非小细胞肺癌（nsclc）和374例乳腺癌（bc）的肿瘤细胞、基质细胞和肿瘤浸润白细胞（til）中的SYK激酶进行了空间定位。我们建立了局部SYK与临床病理变量和结果的关联。通过体外细胞因子刺激、转录组学分析和使用小分子抑制剂选择性阻断SYK，评估SYK对肿瘤细胞的免疫调节作用。用肿瘤细胞与外周血淋巴细胞共培养来评估功能反应。还研究了在I期临床试验中接受SYK抑制剂治疗的BC患者的基线和治疗后活检中的T细胞反应。在非小细胞肺癌和BC中，肿瘤细胞或白细胞SYK表达升高与高CD4+和CD8+ TILs以及更好的预后相关。在肺腺癌中，肿瘤细胞SYK与EGFR或KRAS的致癌驱动突变相关，而在BC中，SYK与三阴性表型相关。在培养的肿瘤细胞中，SYK被TNFα上调，是TNFα诱导的促炎反应和T细胞活化所必需的。在一项包括3例晚期三阴性BC患者的I期临床试验中，纳武单抗后SYK阻断可降低til和T细胞增殖。我们的工作确定了肿瘤细胞SYK在肺癌和乳腺癌中的促炎功能。SYK信号在培养的肿瘤细胞中是T细胞激活所必需的，SYK阻断限制了癌症患者的适应性抗肿瘤免疫反应和肿瘤排斥反应。总之，我们的研究结果确立了SYK表达在人实体瘤中的免疫调节作用。这些信息可用于开发新的生物标志物和/或治疗策略。
The expression of SYK in cancer cells has been associated with both tumor promoting and tumor suppressive effects. Despite being proposed as anticancer therapeutic target, the possible role of SYK in modulating local adaptive antitumor immune responses remains uncertain. Using detailed analysis of primary human tumors and in vitro models, we reveal the immunomodulatory effect of SYK protein in human solid cancer. We spatially mapped SYK kinase in tumor cells, stromal cells and tumor-infiltrating leukocytes (TILs) in 808 primary non-small cell lung carcinomas (NSCLCs) from two cohorts and in 374 breast carcinomas (BCs) from two independent cohorts. We established the associations of localized SYK with clinicopathologic variables and outcomes. The immunomodulatory role of SYK on tumor cells was assessed using in vitro cytokine stimulation, transcriptomic analysis and selective SYK blockade using a small molecule inhibitor. Functional responses were assessed using cocultures of tumor cells with peripheral blood lymphocytes. T cell responses in baseline and post-treatment biopsies from patients with BC treated with a SYK inhibitor in a phase I clinical trial were also studied. Elevated tumor cell or leukocyte SYK expression was associated with high CD4+ and CD8+ TILs and better outcome in both NSCLC and BC. Tumor cell SYK was associated with oncogenic driver mutations in EGFR or KRAS in lung adenocarcinomas and with triple negative phenotype in BC. In cultured tumor cells, SYK was upregulated by TNFα and required for the TNFα-induced proinflammatory responses and T cell activation. SYK blockade after nivolumab in a phase I clinical trial including three patients with advanced triple negative BC reduced TILs and T cell proliferation. Our work establishes the proinflammatory function of tumor cell SYK in lung and breast cancer. SYK signaling in cultured tumor cells is required for T cell activation and SYK blockade limits adaptive antitumor immune responses and tumor rejection in patients with cancer. Together, our results establish the immunomodulatory role of SYK expression in human solid tumors. This information could be used to develop novel biomarkers and/or therapeutic strategies.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
50.3
作者：
Singh A;Greninger P;Rhodes D;Koopman L;Violette S;Bardeesy N;Settleman J
通讯作者：
Settleman J
DOI：
10.1158/1078-0432.ccr-17-2542
发表时间：
2018-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Villarroel-Espindola F;Yu X;Datar I;Mani N;Sanmamed M;Velcheti V;Syrigos K;Toki M;Zhao H;Chen L;Herbst RS;Schalper KA
通讯作者：
Schalper KA
DOI：
10.4049/jimmunol.1700893
发表时间：
2017-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jurtz V;Paul S;Andreatta M;Marcatili P;Peters B;Nielsen M
通讯作者：
Nielsen M
影响因子：
11.2
作者：
Hong J;Yuan Y;Wang J;Liao Y;Zou R;Zhu C;Li B;Liang Y;Huang P;Wang Z;Lin W;Zeng Y;Dai JL;Chung RT
通讯作者：
Chung RT