Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide, and its occurrence is related to the accumulation of gene mutations and immune escape of the tumor. Sequencing of the T-cell receptor (TCR) repertoire can reveal the immunosurveillance status of the tumor microenvironment, which is related to tumor escape and immunotherapy. This study aimed to determine the characteristics and clinical significance of the TCR repertoire in lung cancer. To comprehensively profile the TCR repertoire, results from high-throughput sequencing of samples from 93 Chinese patients with lung cancer were analyzed. We found that the TCR clonality of tissues was related to smoking, with higher clonality in patients who had quit smoking for less than 1 year. As expected, TCR clonality was correlated with stages: patients with stage IV disease showed higher clonality than others. The correlation between TCR repertoire and epidermal growth factor receptor (EGFR) status was also investigated. Patients with EGFR non-L858R mutations showed higher clonality and a lower Shannon index than other groups, including patients with EGFR L858R mutation and wild-type EGFR. Furthermore, we analyzed the TCR similarity metrics—that is, the TCR shared between postoperative peripheral blood and tissue of patients with non-distant metastasis of lung cancer. A similar trend was found, in which patients with EGFR L858R mutations had lower overlap index (OLI) and Morisita index (MOI) scores. Moreover, the OLI showed a positive correlation with several clinical characteristics, including the tumor mutational burden of tissues and the maximum somatic allele frequency of blood; OLI showed a negative correlation with the ratio of CD4+CD28+ in CD4+ cells and the ratio of CD8+CD28+ in CD8+ cells. In conclusion, TCR clonality and TCR similarity metrics correlated with clinical characteristics of patients with lung cancer. Differences in TCR clonality, Shannon index, and OLI across EGFR subtypes provide information to improve understanding about varied responses to immunotherapy in patients with different EGFR mutations.
Highlights
Accumulation of gene mutations and tumor escape from immunosurveillance are the main causes of tumors
There was a negative, and nonsignificant, correlation trend (Spearman r=−0.334; p=0.150; Supplementary Figure 3). These results suggest that patients with advanced lung cancer have higher T-cell receptor (TCR) clonality and that the clonality of the TCR repertoire is closely associated with tumor stage
Our data do not yet indicate whether TCR similarity metrics are associated with prognosis, and more population survival information is needed to confirm the prognostic value of the TCR repertoire. These findings indicate that the TCR similarity metrics were closely associated with clinical characteristics and gene mutations; low overlap index (OLI) or Jaccard index (JI) scores correlated with a favorable clinical status, suggesting that these indices may have the potential to predict patient prognosis
Summary
Accumulation of gene mutations and tumor escape from immunosurveillance are the main causes of tumors. Because of the great success of immune-checkpoint blockers in improving survival in patients with lung cancer, more attention has been paid to the mechanism of immune escape, and finding biomarkers that can effectively predict the efficacy of immunotherapy has become an important goal [2,3,4]. With the wide application of immunotherapies in lung cancer, including as first-line and adjuvant therapies, programmed death ligand 1 and tumor mutational burden (TMB) are no longer sufficient to predict therapeutic outcomes; for adjuvant and neoadjuvant therapy, their predictive efficiency is only 20%–50% in patients with advanced disease [5, 6]. Additional investigation of the T-cell receptor (TCR) repertoire could provide more insight into tumor immunity and might provide new biomarkers to predict the efficacy of immunotherapy
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