Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China.
Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China.
Cancer Immunol Immunother. 2023 Dec;72(12):4235-4247. doi: 10.1007/s00262-023-03560-x. Epub 2023 Nov 6.
Neoadjuvant immunotherapy has been demonstrated to be effective and safe in resectable non-small cell lung cancer (NSCLC) patients. However, the presence of different oncogenic driver mutations may affect the tumor microenvironment and consequently influence the clinical benefit from immunotherapy.
This retrospective study included consecutive NSCLC patients (stage IIA to IIIB) who underwent radical surgery after receiving neoadjuvant immunotherapy at a single high-volume center between December 2019 and August 2022. Pathological response and long-term outcomes were compared based on the driver oncogene status, and RNA sequencing analysis was conducted to investigate the transcriptomic characteristics before and after treatment.
Of the 167 patients included in this study, 47 had oncogenic driver mutations. KRAS driver mutations were identified in 28 patients, representing 59.6% of oncogenic driver mutations. Of these, 17 patients had a major pathological response, which was significantly higher than in the non-KRAS driver mutation group (60.7% vs. 31.6%, P = 0.049). Multivariate Cox regression analysis further revealed that the KRAS driver mutation group was an independent prognostic factor for prolonged disease-free survival (hazard ratio: 0.10, P = 0.032). The median proportion of CD8 T cells was significantly higher in the KRAS driver mutation NSCLCs than in the non-driver mutation group (18% vs. 13%, P = 0.030). Furthermore, immune-related pathways were enriched in the KRAS driver mutation NSCLCs and activated after immunotherapy.
Our study suggests that NSCLC patients with KRAS driver mutations have a superior response to neoadjuvant immunotherapy, possibly due to their higher immunogenicity. The findings highlight the importance of considering oncogenic driver mutations in selecting neoadjuvant treatment strategies for NSCLC patients.
新辅助免疫治疗已被证明在可切除的非小细胞肺癌（NSCLC）患者中是有效且安全的。然而，不同的致癌驱动基因突变的存在可能会影响肿瘤微环境，从而影响免疫治疗的临床获益。
这项回顾性研究纳入了 2019 年 12 月至 2022 年 8 月期间在单一高容量中心接受新辅助免疫治疗后接受根治性手术的连续 NSCLC 患者（IIA 期至 IIIB 期）。根据驱动癌基因状态比较病理反应和长期结果，并进行 RNA 测序分析以研究治疗前后的转录组特征。
本研究共纳入 167 例患者，其中 47 例存在致癌驱动基因突变。KRAS 驱动基因突变在 28 例患者中检出，占致癌驱动基因突变的 59.6%。其中，17 例患者有主要病理反应，明显高于非 KRAS 驱动基因突变组（60.7%比 31.6%，P=0.049）。多因素 Cox 回归分析进一步表明，KRAS 驱动基因突变组是无病生存期延长的独立预后因素（风险比：0.10，P=0.032）。KRAS 驱动基因突变 NSCLC 中 CD8 T 细胞的中位数比例明显高于非驱动基因突变组（18%比 13%，P=0.030）。此外，KRAS 驱动基因突变 NSCLC 中富集了免疫相关途径，并在免疫治疗后被激活。
我们的研究表明，KRAS 驱动基因突变的 NSCLC 患者对新辅助免疫治疗有更好的反应，可能是因为它们具有更高的免疫原性。这些发现强调了在为 NSCLC 患者选择新辅助治疗策略时考虑致癌驱动基因突变的重要性。
