Oncogenic KRAS impairs anti-tumor immune responses. As effective strategies to combine KRAS inhibitors and immunotherapies have so far proven elusive, a better understanding of how oncogenic KRAS drives immune evasion is needed to identify approaches that could sensitize KRAS-mutant lung cancer to immunotherapy. In vivo CRISPR-Cas9 screening in an immunogenic murine lung cancer model identified mechanisms by which oncogenic KRAS promotes immune evasion, most notably via upregulation of immunosuppressive cyclooxygenase-2 (COX-2) in cancer cells. Oncogenic KRAS potently induced COX-2 in both mouse and human lung cancer, which was suppressed using KRAS inhibitors. COX-2 acted via prostaglandin E2 (PGE2) to promote resistance to immune checkpoint blockade (ICB) in lung adenocarcinoma. Targeting COX-2/PGE2 remodeled the tumor microenvironment by inducing pro-inflammatory polarization of myeloid cells and influx of activated cytotoxic CD8+ T cells, which increased the efficacy of ICB. Restoration of COX-2 expression contributed to tumor relapse after prolonged KRAS inhibition. These results provide the rationale for testing COX-2/PGE2 pathway inhibitors in combination with KRASG12C inhibition or ICB in patients with KRAS-mutant lung cancer.

中文翻译：

---

CRISPR-Cas9 筛选发现 KRAS 诱导的 COX-2 是肺癌免疫治疗耐药性的驱动因素


致癌 KRAS 会损害抗肿瘤免疫反应。由于迄今为止将 KRAS 抑制剂和免疫疗法结合起来的有效策略难以捉摸，因此需要更好地了解致癌 KRAS 如何驱动免疫逃避，以确定可以使 KRAS 突变肺癌对免疫疗法敏感的方法。在免疫原性小鼠肺癌模型中进行体内 CRISPR-Cas9 筛选，确定了致癌 KRAS 促进免疫逃避的机制，最显着的是通过上调癌细胞中的免疫抑制性环氧合酶-2 (COX-2)。致癌 KRAS 在小鼠和人类肺癌中均有效诱导 COX-2，而 KRAS 抑制剂可抑制 COX-2。 COX-2 通过前列腺素 E2 (PGE2) 发挥作用，促进肺腺癌对免疫检查点阻断 (ICB) 的抵抗。靶向 COX-2/PGE2 通过诱导骨髓细胞的促炎极化和活化的细胞毒性 CD8+ T 细胞的流入来重塑肿瘤微环境，从而提高了 ICB 的疗效。长期抑制 KRAS 后，COX-2 表达的恢复导致肿瘤复发。这些结果为在 KRAS 突变肺癌患者中测试 COX-2/PGE2 通路抑制剂与 KRASG12C 抑制或 ICB 组合提供了依据。