The combination of different checkpoint inhibitors has been shown to benefit some patients with non-small cell lung cancer (NSCLC), but identifying those who are most likely to benefit and sparing patients who will not remains a crucial challenge. Skoulidis et al. show that tumors with mutations in KEAP1 and/or STK11 are more likely to respond to dual PD-L1 and CTLA4 blockade (with the inhibitors durvalumab and tremelimumab, respectively) when combined with chemotherapy. This subset of patients did not benefit from chemotherapy and durvalumab together, highlighting the importance of CTLA4 inhibition. In mouse models of NSCLC with mutations in Stk11 or Keap1, the authors observed a distinct portfolio of immune-infiltrating cells in tumors, with specific enrichment of suppressive myeloid cells and a dearth of CD8⁺ cytotoxic T cells. Treatment with anti-PD-1 and anti-CTLA4 antibodies led to potent tumor regression probably mediated by the activation of CD4⁺ T cell subsets and a shift in the myeloid compartment toward cells that kill by the production of inducible nitric oxide synthase. Lung cancers driven by mutations in KEAP1 or STK11 are notoriously challenging to treat, so the identification of a potential therapy regimen that is tailored to these alterations is an encouraging step forward.

Original reference: Nature https://doi.org/10.1038/s41586-024-07943-7 (2024)

不同检查点抑制剂的组合已被证明对一些非小细胞肺癌 （NSCLC） 患者有益，但确定最有可能受益的患者并保留不会受益的患者仍然是一个关键挑战。Skoulidis 等人表明，当与化疗联合使用时，具有 KEAP1 和/或 STK11 突变的肿瘤更有可能对双重 PD-L1 和 CTLA4 阻断（分别为抑制剂 durvalumab 和 tremelimumab）产生反应。这部分患者没有同时从化疗和 durvalumab 中受益，这凸显了 CTLA4 抑制的重要性。在具有 Stk11 或 Keap1 突变的 NSCLC 小鼠模型中，作者观察到肿瘤中独特的免疫浸润细胞组合，抑制性髓系细胞特异性富集，CD8⁺ 细胞毒性 T 细胞缺乏。用抗 PD-1 和抗 CTLA4 抗体治疗导致有效的肿瘤消退，这可能是由 CD4⁺ T 细胞亚群的激活和骨髓区室向通过产生诱导型一氧化氮合酶杀死的细胞转移介导的。众所周知，由 KEAP1 或 STK11 突变驱动的肺癌很难治疗，因此确定针对这些改变量身定制的潜在治疗方案是令人鼓舞的进步。

原文参考：Nature https://doi.org/10.1038/s41586-024-07943-7 （2024）