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Identification of TCR rearrangements specific for genetic alterations in EGFR-mutated non-small cell lung cancer: results from the ADJUVANT-CTONG1104 trial

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Abstract

Tumor response T cells, which have specific T cell receptor (TCR) rearrangements in tumor-infiltrating lymphocytes, determine their ability to interact with the mutation-derived neoantigens presented by antigen-presenting cells. Little is known about the genetic alterations related to specific TCR clones in non-small cell lung cancer (NSCLC) patients who have an epidermal growth factor receptor (EGFR) mutation. In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial for high-throughput TCRβ V region and exome sequencing. Ten clonal TCRs were associated with EGFR exon 19 deletion (del), EGFR exon 21 mutation (L858R), RB1 alteration, TP53 exon 4/5 missense mutation, TP53 nonsense mutation, or copy number gains in NKX2-1 and CDK4. Among the TCRs, there was frequent use of Vβ20-1Jβ2-3 specifically for EGFR exon 19 del or Vβ9Jβ2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting. Moreover, in comparison with the chemotherapy-preferable (CP) group, higher frequencies of Vβ20-1Jβ2-3 and Vβ9Jβ2-1 were found in the highly TKI-preferable (HTP) or TKI-preferable (TP) groups. Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vβ20-1Jβ2-3 or Vβ9Jβ2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82202997, 82002413), Guangdong Provincial Applied Science and Technology Research & Development Program (No. 2016B020237006), China Postdoctoral Science Foundation (No. 2021M701422), Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine (No. 2017B030314120), and CTONG- MSD Lung Cancer Research Grant (No. CTONG-YC20210201).

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  1. Cunte Chen and Siyang Maggie Liu have contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China

    Cunte Chen, Siyang Maggie Liu, Ling Xu, Yikai Zhang & Yangqiu Li

  2. Department of Hematology, First Affiliated Hospital, The Clinical Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China

    Siyang Maggie Liu & Yangqiu Li

  3. Chinese Thoracic Oncology Group (CTONG), Guangzhou, 510055, China

    Siyang Maggie Liu

  4. Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, 210032, China

    Yedan Chen, Qiuxiang Ou, Hua Bao & Yang Shao

  5. Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China

    Jia-Tao Zhang, Wenzhao Zhong, Qing Zhou, Xue-Ning Yang, Yi-Long Wu & Si-Yang Liu

  6. School of Public Health, Nanjing Medical University, Nanjing, 211166, China

    Yang Shao

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  1. Cunte Chen
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Contributions

YQL, YLW, and SYL: contributed to the concept development and study design and edited the manuscript. CTC and SYML: interpreted the data and wrote the manuscript. YDC: drafted the Methods and revised the manuscript. QXO: developed the TCR test, performed initial data analysis, and helped edit the manuscript. HB: initial bioinformatic data analysis and reviewed the statistical methodologies and results. JTZ, LX and YKZ: interpreted the data. MH: review and helped edit the manuscript. WZZ, QZ, and XNY: diagnosed and treated the patients and provided clinical samples. YS: supervised data analysis and manuscript editing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yi-Long Wu, Si-Yang Liu or Yangqiu Li.

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Conflict of interest

Yi-Long Wu discloses the following personal financial interest: Consulting and advisory services, speaking engagements for Roche, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Sanofi, MSD, and BMS. Yedan Chen, Qiuxiang Ou, Hua Bao and Yang Shao are the employees of Nanjing Geneseeq Techology Inc.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Guangdong Provincial People's Hospital (No. 2011713).

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Written informed consent was received from participants before inclusion in the study. Participants were identified by number, not by name.

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Chen, C., Liu, S.M., Chen, Y. et al. Identification of TCR rearrangements specific for genetic alterations in EGFR-mutated non-small cell lung cancer: results from the ADJUVANT-CTONG1104 trial. Cancer Immunol Immunother 72, 1261–1272 (2023). https://doi.org/10.1007/s00262-022-03330-1

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