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The impact of oncogenic driver mutations on neoadjuvant immunotherapy outcomes in patients with resectable non-small cell lung cancer

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Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

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Data availability

RNA sequencing data were deposited in the Genome Sequence Archive database under accession number HRA002071. Data and codes utilized in this study are immediately available from the corresponding author upon reasonable request.

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Funding

This research was supported by the National Natural Science Foundation of China (Grant no. 82125001), the Innovation Program of Shanghai Municipal Education Commission (Grant no. 2023ZKZD33), Clinical Research foundation of Shanghai Pulmonary Hospital (Grant no. FKLY20004), and Science and Technology Commission of Shanghai Municipality (Grant no. 23YF1435200).

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Author notes

  1. Ziyun Shen, Meixin Teng and Lu Han contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China

    Ziyun Shen, Lu Han, Dongliang Bian, Jing Zhang, Xinsheng Zhu, Yan Chen, Wangchao Yao & Peng Zhang

  2. Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China

    Ziyun Shen, Lele Zhang & Peng Zhang

  3. Shihezi University School of Medicine, Shihezi, 832002, Xinjiang, China

    Meixin Teng & Yang Qing

  4. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China

    Shiqi Hu

  5. Experimental Animal Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China

    Huansha Yu

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  1. Ziyun Shen
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Contributions

Concept and design were contributed by ZS, LZ and PZ; Acquisition of data was contributed by ZS, MT, DB, JZ, XZ, YQ, SH, YC, WY and HY; Analysis and interpretation of clinical data and RNA sequencing data were contributed by ZS, MT and LH; Drafting of the manuscript was contributed by ZS and LZ. Critical revision was contributed by ZS, MT, LH, LZ and PZ. Funding acquisition was contributed by ZS and PZ. All authors contributed to the article and approved the submitted version.

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Correspondence to Lele Zhang or Peng Zhang.

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Shen, Z., Teng, M., Han, L. et al. The impact of oncogenic driver mutations on neoadjuvant immunotherapy outcomes in patients with resectable non-small cell lung cancer. Cancer Immunol Immunother 72, 4235–4247 (2023). https://doi.org/10.1007/s00262-023-03560-x

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