Purpose: Co-mutations of the KRAS and STK11 genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. While neoadjuvant chemoimmunotherapy is now a standard of care treatment for resectable NSCLC, the clinical and immunologic impact of KRAS andSTK11 co-mutations in this setting are unknown. Experimental design: We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occuring STK11 mutations, treated with neoadjuvant ICB. Single cell transcriptomics was performed on tumor-infiltrating T cells from 7 KRASmut/STK11wttumors and 6 KRASmut/STK11mut tumors. Results: Relative to KRASmut/STK11wttumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased PGE-2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TIL from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT). Conclusions: These divergent T cell transcriptional fates suggest T cell maintenance and residence may be detrimental to anti-tumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning PGE-2 and IL-2 signaling as they relate to T cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.

中文翻译：

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新辅助免疫检查点阻断后可切除 KRAS 突变肺癌中基于 STK11 共突变状态的不同临床和免疫学结果


目的：晚期非小细胞肺癌 （NSCLC） 中 KRAS 和 STK11 基因的共突变与免疫检查点阻断 （ICB） 耐药有关。虽然新辅助化学免疫疗法现在是可切除 NSCLC 的标准治疗，但在这种情况下 KRAS 和 STK11 共突变的临床和免疫学影响尚不清楚。实验设计： 我们评估并比较了新辅助 ICB 治疗可切除的 KRAS 突变 NSCLC 肿瘤的无复发生存期，有或没有同时发生的 STK11 突变。对来自 7 例 KRASmut/STK11wt 肿瘤和 6 例 KRASmut/STK11mut 肿瘤的肿瘤浸润 T 细胞进行单细胞转录组学。结果： 相对于 KRASmut/STK11wttumors，KRASmut/STK11mut 的复发风险显著升高。单细胞转录组学显示氧化磷酸化增强，有证据表明 KRASmut/STK11mut 肿瘤的 CD8+ 肿瘤浸润淋巴细胞 （TIL） 中 PGE-2 信号传导减少，IL-2 信号传导增加，这一发现也反映在复发的 KRASwt 肿瘤中。来自 KRASmut/STK11mut 肿瘤的 TIL 表达高水平的与肿瘤居住相关的分子，包括 CD39 和 ZNF683 （HOBIT）。结论： 这些不同的 T 细胞转录命运表明，在可切除 NSCLC 的新辅助 ICB 背景下，T 细胞的维持和驻留可能不利于抗肿瘤免疫，无论 KRAS 突变状态如何。我们的工作为未来研究 PGE-2 和 IL-2 信号传导的基础机制提供了基础，因为它们与 T 细胞对癌症的免疫有关，以及接受新辅助 ICB 治疗的 KRASmut/STK11mut NSCLC 的不同临床结果。