Alterations of TMB and TCR repertoires during chemotherapy in East Asian lung cancer patients without TKI-related driver gene mutations

Abstract

Abstract Background Tumor mutation burden (TMB) and T cell receptor (TCR) diversity have been suggested as predictive biomarkers in cancer immunotherapy. It is not clear how chemotherapy influences TMB, and how TMB or clinical factors correlate with TCR clonality. The aim of this study is to investigate the relationship between TMB and TCR clonality and to provide suggestions for patient selection and the opportunity to start immunotherapy in East Asian late-stage lung cancer patients with first-line chemotherapy. Methods 43 NSCLC patients and 18 SCLC patients with no TKI-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET) mutations were enrolled in this study. Genomic variations and TMB were determined with lung cancer tissue by whole-exome sequencing (WES). TCR sequencing was also performed with peripheral blood samples. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P\xa0≤\xa00.05 was regarded as statistically significant. Results The mutation spectrums were changed dramatically after chemotherapy in NSCLC patients. Chemotherapy appeared to cause decreases in the positive detection rate of mutated genes. Significant decrease in TMB from mean value of 3.67 to 1.95 were observed after chemotherapy in these NSCLC patients (p\xa0=\xa00.05), and patients can be dichotomized based on TMB decrease extent. The relationship between TCR clonality and TMB or clinical factors were also explored in NSCLC and SCLC patients. The number of TCR clones was not correlated with TMB, gender, age, metastasis, lung cancer subtype or therapeutic response (p\xa0>\xa00.05). However, it was dramatically higher in patients with smoking history than those with no smoking history (p\xa0=\xa00.01). Conclusions This study suggested that chemotherapy could alter the genomic profiles and TMB dramatically. Patients with decreased TMB after the first-line chemotherapy may be less likely to benefit from immunotherapy. Non-smokers with higher TCR diversity than smokers may be more likely to benefit from immunotherapy. Since the number of TCR clones was not correlated with TMB, it is still worth investigating whether TMB or TCR clonality, or both combined is a better predictive biomarker for immunotherapy. Legal entity responsible for the study The authors. Funding This study was supported in part by a grant from National Natural Science Foundation of China (81802255), Shanghai Pujiang Program (17PJD036) and a grant from Shanghai Municipal Commission of Health and Family Planning Program (20174Y0131). National key research & development project (2016YFC0902300). Major disease clinical skills enhancement program of three-year action plan for promoting clinical skills and clinical innovation in municipal hospitals, Shanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC (16CR1001A). The fundamental research funds for the central universities. Disclosure All authors have declared no conflicts of interest.