Comprehensive analysis of T cell receptor repertoire in patients with KRAS mutant non-small cell lung cancer

Yadong Wang; Ling Peng; Ming Zhao; Yuanyuan Xiong; Jianchao Xue; Bowen Li; Zhicheng Huang; Xinyu Liu; Xiaoying Yang; Yang Song; Zhongxing Bing; Chao Guo; Zhenhuan Tian; Chao Gao; Lei Cao; Zhili Cao; Ji Li; Xu Jiang; Xiaoyan Si; Li Zhang; Xiaoguang Li; Zhibo Zheng; Mengmeng Song; Rongrong Chen; Wan-Teck Lim; Alberto Pavan; Atocha Romero; Naixin Liang; Huaxia Yang; Shanqing Li

doi:10.21037/tlcr-22-629

Comprehensive analysis of T cell receptor repertoire in patients with KRAS mutant non-small cell lung cancer

Transl Lung Cancer Res. 2022 Sep;11(9):1936-1950. doi: 10.21037/tlcr-22-629.

Authors

Yadong Wang^#^{1

2}, Ling Peng^#³, Ming Zhao^#⁴, Yuanyuan Xiong^#⁵, Jianchao Xue^{1

2}, Bowen Li^{1

2}, Zhicheng Huang^{1

2}, Xinyu Liu^{1

6}, Xiaoying Yang^{1

6}, Yang Song¹, Zhongxing Bing¹, Chao Guo¹, Zhenhuan Tian¹, Chao Gao¹, Lei Cao¹, Zhili Cao¹, Ji Li⁷, Xu Jiang^{8

9}, Xiaoyan Si¹⁰, Li Zhang¹⁰, Xiaoguang Li¹¹, Zhibo Zheng^{1

12}, Mengmeng Song⁵, Rongrong Chen⁵, Wan-Teck Lim¹³, Alberto Pavan¹⁴, Atocha Romero¹⁵, Naixin Liang¹, Huaxia Yang^{9

16}, Shanqing Li¹

Affiliations

¹ Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
⁴ Department of Thoracic Surgery, the General Hospital of the People's Liberation Army, Beijing, China.
⁵ Geneplus-Beijing, Beijing, China.
⁶ Eight-Year MD Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁷ Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁸ Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁹ State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹⁰ Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹¹ Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹² Department of International Medical Services, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹³ Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
¹⁴ Medical Oncology Department, AULSS 3 Serenissima, Mestre-Venezia, Italy.
¹⁵ Medical Oncology Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain.
¹⁶ Department of Rheumatology and Clinical Immunology, National Clinical Research Center for Dermatologic and Immunologic Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, the Ministry of Education Key Laboratory, Beijing, China.

^# Contributed equally.

Abstract

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in non-small cell lung cancer (NSCLC). The administration of immunotherapy has demonstrated significant efficacy in prolonging the overall survival of patients with KRAS mutation in recent years. However, the efficacy of immunotherapy in KRAS mutant NSCLC is variable. Analysis of T cell receptor (TCR) repertoire may contribute to a better understanding of the mechanisms behind such differential outcomes.

Methods: A total of 47 patients with KRAS mutant NSCLC were enrolled in this study. Deep sequencing of the TCR β chain complementarity-determining regions in tumor tissue and paired peripheral blood specimens was conducted. Comprehensive analysis of TCR repertoire metrics was performed with different KRAS mutation subtypes and concomitant mutations. Moreover, the associations between TCR repertoire metrics and tumor mutation burden (TMB), as well as programmed death-ligand 1 were explored, respectively.

Results: TCR repertoire metrics, including Shannon index, Clonality, and Morisita index (MOI), showed no significant differences among different KRAS mutation subtypes. The similar results were observed between patients with tumor protein p53 (TP53) mutation and those with wild-type TP53. In contrast, although no significant differences were found in Shannon index and Clonality, patients with KRAS/serine/threonine kinase 11 (STK11) comutation showed a significantly higher MOI compared to their STK11 wild-type counterparts (P=0.012). In addition, TCR repertoire metrics were neither associated with TMB nor programmed death-ligand 1 expression in KRAS mutant NSCLC.

Conclusions: This retrospective study comprehensively described the TCR repertoire in KRAS mutant NSCLC. A higher MOI represented more overlap of the TCR repertoire between tumor tissue and paired peripheral blood, indicating distinctive immunological features in NSCLC with KRAS/STK11 comutation.

Keywords: Kirsten rat sarcoma viral oncogene homolog (KRAS); T cell receptor repertoire (TCR repertoire); immunotherapy; mutations; non-small cell lung cancer (NSCLC).