Dynamic changes in the T cell receptor repertoire during treatment with radiotherapy combined with an immune checkpoint inhibitor

Abstract

Previous studies have indicated a synergistic effect between radiotherapy and immunotherapy. A better understanding of how this combination affects the immune system can help to clarify its role in the treatment of metastatic cancer. We performed T cell receptor (TCR) sequencing on 46 sequentially collected samples from 15 patients with stage IV non-small cell lung cancer, receiving stereotactic body radiotherapy combined with a programmed cell death ligand-1 (PD-L1) inhibitor. TCR repertoire diversity was assessed using Rényi diversity curves and the Shannon diversity index. TCR clones were tracked over time. We found decreasing or stable diversity in the best responders, and an increase in diversity at progression in patients with an initial response. Expansion of TCR clones was more often seen in responders. Several patients also developed new clones of high abundance. This seemed to be more related to radiotherapy than to immune checkpoint blockade. In summary, we observed similar dynamics in the TCR repertoire as have been described with immunotherapy alone. In addition, the occurrence of new unique clones of high abundance after radiotherapy may indicate that radiotherapy functions as a personalized cancer vaccine.

Combined chemoradiotherapy and programmed cell death‐ligand 1 blockade leads to changes in the circulating T‐cell receptor repertoire of patients with non‐small‐cell lung cancer

“…Archived biopsy samples were limited and sequencing of tumor‐infiltrating TCRs was unsuccessful. In a mouse tumor model, combined radiation therapy and ICB expanded the numbers of tumor‐reactive CD8 + T cells, leading to their infiltration at the tumor site 10 . Likewise, peripheral T cells expanded by the combination therapy recognized neoantigens, infiltrating the tumor sites in patients with NSCLC 8 .…”

“…In a mouse tumor model, combined radiation therapy and ICB expanded the numbers of tumor‐reactive CD8 + T cells, leading to their infiltration at the tumor site. 10 Likewise, peripheral T cells expanded by the combination therapy recognized neoantigens, infiltrating the tumor sites in patients with NSCLC. 8 Lussier et al recently reported that mutations elicited by radiation give rise to neoantigens presented by MHC molecules.…”

Comparison of the tumor immune microenvironment and checkpoint blockade biomarkers between stage III and IV non-small cell lung cancer

“…There are also several ICB-related factors to explore with next-generation sequencing that were not broached in these analyses. Relationships between circulating tumor cells [ 43 ], T cell receptor repertoires [ 44 ], and/or homologous recombination deficiency with ICB treatment have all been described [ 45 ], and further comparisons between stage III and IV TIMEs should consider these molecular characteristics. Regarding clinical characteristics, the data presented here are from pretreatment tumors.…”

T-Cell Repertoire in Tumor Radiation: The Emerging Frontier as a Radiotherapy Biomarker

“…Dynamic changes to the TCR repertoire by RT were revealed by analyzing longitudinal peripheral blood samples, which showed increased frequencies of the top 10 TCR clonotypes post-RT, thus supporting the notion that radiation promotes peripheral expansion of tumor-resident T-cell clones. TCR sequencing was also performed in longitudinal blood samples from NSCLC patients receiving RT combined with anti-PD-L1 treatment; in this case, expansion of TCR clones was more frequent in treatment responders and was accompanied by a decreased TCR clonotype [ 80 ]. On the contrary, patients who clinically progressed after an initial response to therapy presented with increased TCR clonotype diversity [ 80 ].…”

“…TCR sequencing was also performed in longitudinal blood samples from NSCLC patients receiving RT combined with anti-PD-L1 treatment; in this case, expansion of TCR clones was more frequent in treatment responders and was accompanied by a decreased TCR clonotype [ 80 ]. On the contrary, patients who clinically progressed after an initial response to therapy presented with increased TCR clonotype diversity [ 80 ]. These results demonstrate that RT may induce dynamic changes in the TCR repertoire via specific recognition of released tumor peptides from dying tumor cells resulting in systemic tumor responses.…”