Background: EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment. Methods: Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in murine models of non-small cell lung cancer (NSCLC). Results: Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrates via flow cytometry revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T-cell activation, particularly in CD8+ T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1 in RNA expression analyses. Conclusions: Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit the activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape.
背景：EphA2是一种受体酪氨酸激酶，在肿瘤生长和转移中发挥重要作用，已被确定为多种实体瘤的潜在治疗靶点。探究EphA2对宿主免疫系统的影响，有助于深化我们对肿瘤免疫逃逸机制以及靶向EphA2对肿瘤微环境影响的理解。方法：本研究通过非小细胞肺癌小鼠模型，探讨肿瘤特异性EphA2对免疫细胞群活化与浸润、以及细胞因子和趋化因子微环境的影响。结果：尽管非小细胞肺癌细胞中EphA2的过表达在体外未显示增殖优势，但在体内却赋予肿瘤生长优势。通过流式细胞术分析肺肿瘤浸润免疫细胞发现，EphA2过表达肿瘤中自然杀伤细胞和T细胞减少，而髓系细胞群（包括肿瘤相关巨噬细胞）增多。T细胞（尤其是CD8+ T细胞）的活化程度降低，同时PD-1表达增加。RNA表达分析显示，这些变化伴随着单核细胞趋化因子（特别是CCL2、CCL7、CCL8和CCL12）以及免疫抑制蛋白TGF-β和精氨酸酶1的表达上调。结论：我们的研究表明，肿瘤细胞上的EphA2能够招募单核细胞并促进其分化为肿瘤相关巨噬细胞，这可能抑制细胞毒性淋巴细胞的活化和浸润，从而促进肿瘤免疫逃逸。
肿瘤(癌症)患者之家