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首页> 外文期刊>Oncoimmunology. >Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer
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Crk adaptor protein promotes PD-L1 expression, EMT and immune evasion in a murine model of triple-negative breast cancer

机译：Crk适配器蛋白在三阴性乳腺癌的小鼠模型中促进PD-L1表达，EMT和免疫逃避

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The tumor infiltration of immune cells in solid cancers can profoundly influence host antitumor responses. In recent years, immunotherapeutic regimens, that target immune checkpoints, demonstrated significant antitumor response by increasing intra-tumoral immune cell populations, including CD8+ effector T cells. However, administration of such immune checkpoint inhibitors is largely inefficacious in inducing immunogenicity and treating breast cancer. Currently, there is a great need to better understand cell autonomous mechanisms of immune evasion in breast cancer to identify upstream therapeutic targets that increase the efficacy of immunotherapy. Here we show that Crk, an SH2 and SH3 domain-containing adaptor protein implicated in focal adhesion signaling, cell migration, and invasion, and frequently up-regulated in human cancers, has an important role in regulating the tumor immune microenvironment. Using a murine 4T1 breast adenocarcinoma model of spontaneous metastasis in immune-competent BALB/C mice, we show that genetic ablation of Crk by CRISPR-Cas9 leads to enhanced anti-tumor immune cell populations, cytotoxic effector and immune surveillance cytokines in primary tumor. Pathologically, this leads to a significant reduction in tumor growth and lung metastasis. Mechanistically, Crk KO suppresses EMT and PD-L1 expression on tumor cells and acts additively with anti-PDI therapy to suppress tumor growth and metastasis outcomes. Taken together, these data reveal a previously un-described function of Crk adaptor protein expression in tumor cells for cell autonomous regulation of tumor immune microenvironment.
机译：在固体癌中的免疫细胞肿瘤浸润可以深刻地影响宿主抗肿瘤反应。近年来，靶免疫检查点的免疫治疗方案通过增加肿瘤内免疫细胞群，包括CD8 +效应T细胞来表现出显着的抗肿瘤反应。然而，在诱导免疫原性和治疗乳腺癌时，这种免疫检查点抑制剂的给药在很大程度上。目前，有很大的需要更好地了解乳腺癌中免疫逃逸的细胞自主机制，以确定增加免疫疗法疗效的上游治疗靶标。在这里，我们表明CRK，含SH3和SH3结构域的衔接蛋白涉及局灶性粘附信号，细胞迁移和侵袭，并且在人类癌症中经常上调，在调节肿瘤免疫微环境方面具有重要作用。使用免疫竞争力的BALB / C小鼠的自发转移的鼠4T1乳腺腺癌模型，我们表明CRAP-CAS9的CRK遗传消融导致原发性肿瘤中的抗肿瘤免疫细胞群，细胞毒性效应和免疫监测细胞因子。病理上，这导致肿瘤生长和肺转移的显着降低。机械地，Crk KO抑制肿瘤细胞上的EMT和PD-L1表达，并用抗PDI疗法加剧，以抑制肿瘤生长和转移结果。总之，这些数据揭示了先前未描述的CRK适配器蛋白表达在肿瘤细胞中的CRK适配器蛋白表达的功能，用于肿瘤免疫微环境的细胞自主调节。

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