Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS.
Enhancing anticancer activity of checkpoint immunotherapy by targeting RAS.
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作者：
Ward AB;Keeton AB;Chen X;Mattox TE;Coley AB;Maxuitenko YY;Buchsbaum DJ;Randall TD;Zhou G;Piazza GA
大约30%的人类癌症在RAS基因中存在功能获得性突变，导致RAS蛋白的组成性激活以刺激下游信号传导，包括驱动癌细胞增殖和转移的RAS有丝分裂原活化蛋白激酶途径。RAS驱动的肿瘤发生还通过增加程序性细胞死亡配体-1的表达、减少向T淋巴细胞呈递抗原的主要组织相容性复合物分子的表达以及改变促进免疫抑制细胞类型（例如髓源性抑制细胞、调节性T细胞和癌症相关成纤维细胞）的分化和积累的细胞因子的表达来促进免疫逃避。总之，这些变化导致免疫抑制性肿瘤微环境，阻碍T细胞活化和浸润，并促进肿瘤细胞的生长和转移。因此，尽管检查点免疫疗法越来越成功，但许多RAS驱动的肿瘤患者对治疗产生耐药性，临床结局较差。因此，开发中的RAS抑制剂有可能削弱癌细胞免疫逃避并增强抗肿瘤免疫应答，以改善RAS驱动的癌症患者的生存期。这篇综述强调了RAS抑制剂增强或扩大目前可用的检查点免疫疗法的抗癌活性的潜力。 抑制致癌RAS信号传导增加抗肿瘤免疫。致癌RAS信号传导的抑制导致抗肿瘤免疫和肿瘤细胞凋亡的增加，这是由于细胞毒性T细胞浸润到肿瘤部位的增加、TREG和髓源性抑制细胞的免疫抑制活性的降低以及肿瘤促进癌症相关成纤维细胞的减少。
Approximately 30% of human cancers harbor a gain‐in‐function mutation in the RAS gene, resulting in constitutive activation of the RAS protein to stimulate downstream signaling, including the RAS‐mitogen activated protein kinase pathway that drives cancer cells to proliferate and metastasize. RAS‐driven oncogenesis also promotes immune evasion by increasing the expression of programmed cell death ligand‐1, reducing the expression of major histocompatibility complex molecules that present antigens to T‐lymphocytes and altering the expression of cytokines that promote the differentiation and accumulation of immune suppressive cell types such as myeloid‐derived suppressor cells, regulatory T‐cells, and cancer‐associated fibroblasts. Together, these changes lead to an immune suppressive tumor microenvironment that impedes T‐cell activation and infiltration and promotes the outgrowth and metastasis of tumor cells. As a result, despite the growing success of checkpoint immunotherapy, many patients with RAS‐driven tumors experience resistance to therapy and poor clinical outcomes. Therefore, RAS inhibitors in development have the potential to weaken cancer cell immune evasion and enhance the antitumor immune response to improve survival of patients with RAS‐driven cancers. This review highlights the potential of RAS inhibitors to enhance or broaden the anticancer activity of currently available checkpoint immunotherapy. Inhibition of oncogenic RAS signaling increases antitumor immunity. Inhibition of oncogenic RAS signaling results in an increase in antitumor immunity and tumor apoptosis due to an increase in cytotoxic T‐cell infiltration to the tumor site, a decrease in the immunosuppressive activity of TREGs and myeloid‐derived suppressor cells, and a decrease in tumor‐promoting cancer‐associated fibroblasts.
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