221P - Chemoradiotherapy induced adaptive anti-tumor T cell immunity in patients with non-small cell lung cancer

Background

Concurrent chemoradiation (CRT) represents a standard treatment for several advanced cancers including non-small cell lung cancer (NSCLC) based on its synergistic cytotoxic effects. CRT followed by durvalumab (anti-PD-L1 antibody) therapy has become standard maintenance therapy for locally advanced NSCLC. However, this combination is still ineffective in most patients, illustrating the need to better understand the immunological effects driven by CRT, which are less known. This study aims at investigating the CRT-induced tumor reactive T cell responses as well as transcriptomic changes.

Methods

Blood samples were collected from 43 NSCLC patients at baseline, during CRT, and three months after CRT. For patients received durvalumab after CRT, additional samples were taken at three months and one-year post-durvalumab. Multiparametric immunologic analyses were conducted by IFN-γ ELISpot, RNA-Seq, and qRT-PCR.

Results

A transient decrease in specific T cell responses against TERT and NY-ESO-1 was observed during CRT, followed by an increase after CRT in 60.0% and 40.0% patients, respectively. There was no significant change in antiviral T cell responses before and during CRT. The application of durvalumab can enhance the anti-tumor specific T cell response of CRT. T cell transcriptomic analysis revealed 105 and 422 genes were upregulated during and after CRT compared to baseline, and 81 and 60 genes were downregulated, respectively. There were 16 genes downregulated during CRT but upregulated after which were enriched in inflammatory pathways. Analysis of immune-related genes showed T cell activation, cytolytic, and exhaustion markers were downregulated during CRT but upregulated afterward. RNA-Seq findings were corroborated by qRT-PCR, which identified the relationships between CD8a expression and cytotoxic genes as well as activation markers. TCR-Seq analysis demonstrated CRT induced changes in specificity and diversity of T cell repertoire, with reduced clonotype sharing between patients and an expansion of T cell clones post CRT.

Conclusions

These findings indicate the systemic immunological changes induced by CRT in NSCLC patients support the rationale to use checkpoint inhibitors as adjuvant therapy post CRT.

Legal entity responsible for the study

Olivier Adotevi.

Funding

Ligue Contre Le Cancer.

Disclosure

All authors have declared no conflicts of interest.