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Abstract：
RAS-MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti-CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single-agent treatment in vivo. Combining MAPKi and anti-CD73 was accompanied by significant alterations in intratumor immune cell composition, supporting the effect of MAPKi-induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi-treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti-CD73 and MAPKi treatment.
摘要：
RAS-MAPK信号促进免疫逃避和癌细胞存活，和MAPK抑制剂(MAPKis)经常被用作癌症治疗。尽管有进展阐明了MAPKi对免疫细胞的直接影响，它们通过改变肿瘤细胞对肿瘤微环境（TME）的间接影响仍未完全了解。这里,我们提供的证据表明,由持续的p38MAPK信号传导驱动的对MAPKi的快速代偿反应,癌细胞可以上调免疫抑制蛋白CD73,从而降低抗肿瘤免疫反应.这种补偿性反应也导致对MAPKi的敏感性降低，and,因此,与单药治疗相比,联合使用抗CD73抗体和MAPKi可显著增强体内抗肿瘤效果.MAPKi和抗CD73的结合伴随着肿瘤内免疫细胞组成的显著改变，支持MAPKi诱导的CD73表达对TME的影响。我们表明，在MAPKi治疗的结直肠癌患者中，高CD73表达与较差的预后显着相关。强调MAPKi治疗后CD73表达增加的潜在临床重要性。我们的发现可以解释MAPKi在癌症患者中的作用减弱，并为联合抗CD73和MAPKi治疗提供了进一步的理论基础。
