T-Cell Receptor Profiling and Prognosis After Stereotactic Body Radiation Therapy For Stage I Non-Small-Cell Lung Cancer.

Lirong Wu,Nils-Petter Rudqvist,Rong Yin,Jifeng Feng,James Welsh,Percy Lee,Xuan Pan,Xiangzhi Zhu,Zhongxing Liao,Pansong Li,Ting Xu,Jun Zhu,Ming Jiang,Xia He,Zhipeng Zhou

doi:10.3389/fimmu.2021.719285

Abstract

Radiotherapy is known to influence immune function, including T cell receptor (TCR) repertoire. We evaluated the TCR repertoire before and after stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) and explored correlations between TCR indexes and distant failure after SBRT. TCR repertoires were analyzed in peripheral blood mononuclear cells (PBMCs) collected before and after SBRT from 19 patients. TCR combinational diversity in V and J genes was assessed with multiplex PCR of genomic DNA from PBMCs and tested for associations with clinical response. All patients received definitive SBRT to a biologically effective dose of >=100 Gy. The number of unique TCR clones was decreased after SBRT versus before, but clonality and the Shannon Entropy did not change. Four patients (21%) developed distant metastases after SBRT (median 7 months); those patients had lower Shannon Entropy in post-SBRT samples than patients without metastasis. Patients with a low change in Shannon Entropy from before to after SBRT [(post-SBRT Shannon Entropy minus baseline Shannon)/(baseline Shannon) * 100] had poorer metastasis-free survival than those with high change in Shannon Entropy (P<0.001). Frequencies in V/J gene fragment expression in the TCR β chain were also different for patients with or without metastases (two V fragments in baseline samples and 2 J and 9 V fragments in post-treatment samples). This comprehensive analysis of immune status before and after SBRT showed that quantitative assessments of TCRs can help evaluate prognosis in early-stage NSCLC.

Highlights

Stereotactic body radiotherapy (SBRT), in which ablative doses of radiation are given in a few large fractions to highly conformal targets, is an established treatment option for the management of stage I medically inoperable non-small cell lung cancer (NSCLC) [1]
The number of unique clones was lower after treatment vs. at baseline (Figure 1A), the Shannon Entropy was no difference between patients who did or did not develop metastases (Figure 1C), implying that some fraction of T cell receptor (TCR) clones might experience heterogeneous expansion and others might be eliminated under therapeutic pressure
We report that stereotactic body radiotherapy (SBRT) induced variations in the diversity of the TCR repertoire in patients with stage I non-small-cell lung cancer (NSCLC), and we further found that TCR diversity could predict clinical outcomes after SBRT

Summary

Introduction

Stereotactic body radiotherapy (SBRT), in which ablative doses of radiation are given in a few large fractions to highly conformal targets, is an established treatment option for the management of stage I medically inoperable non-small cell lung cancer (NSCLC) [1]. The excellent local control rates after SBRT for early-stage disease (>90%) are comparable to those after surgery, and the low incidence and severity of short-term or long-term overall toxicity [2] make SBRT a suitable treatment option, especially for patients with poor pulmonary function [3]. SBRT can induce DNA damage [7], and the resulting mutations in cells with DNA mismatch repair deficiency can increase the burden of neoantigens, which in turn trigger an immune response [8]. Immunologic effects may be useful as biomarkers that could be used to distinguish patients for whom tumors could be controlled versus those for whom disease progresses after treatment [12]

Methods

Results

Conclusion