Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients

Abstract

Clinical studies combining radiation and immunotherapy have shown promising response rates, strengthening efforts to sensitize tumors to immune-mediated attack. Thus, there is an ongoing surge in trials using preconditioning regimens with immunotherapy. Yet, due to the scarcity of resected tumors treated in situ with radiotherapy, there has been little investigation of radiation’s sole contributions to local and systemic antitumor immunity in patients. Without this access, translational studies have been limited to evaluating circulating immune subsets and systemic remodeling of peripheral T cell receptor repertoires. This constraint has left gaps in how radiation impacts intratumoral responses and whether tumor-resident T cell clones are amplified following treatment. Therefore, to interrogate the immune impact of radiation on the tumor microenvironment and test the hypothesis that radiation initiates local and systemic expansion of tumor-resident clones, we analyzed renal cell carcinomas from patients treated with stereotactic body radiation therapy. Transcriptomic comparisons were evaluated by bulk RNA sequencing. T cell receptor sequencing monitored repertoires during treatment. Pathway analysis showed radiation-specific enrichment of immune-related processes, and T cell receptor sequencing revealed increased clonality in radiation-treated tumors. The frequency of identified, tumor-enriched clonotypes was tracked across serial blood samples. We observed increased abundance of tumor-enriched clonotypes at 2 wk postradiation compared with pretreatment levels; however, this expansion was not sustained, and levels contracted toward baseline by 4 wk posttreatment. Taken together, these results indicate robust intratumoral immune remodeling and a window of tumor-resident T cell expansion following radiation that may be leveraged for the rational design of combinatorial strategies.

Clonal Expansion of Tumor-Infiltrating T Cells and Analysis of the Tumor Microenvironment within Esophageal Squamous Cell Carcinoma Relapsed after Definitive Chemoradiation Therapy

“…This suggests that the clonal expansion of TIL could be induced by the stimulation of neoantigens derived from tumor cells through the process consisting of cancer antigen presentation, the priming and trafficking of T cells, and infiltration of T cells into tumors, which is commonly known as “the cancer-immunity cycle” reviewed by Chen and Mellman [ 30 ]. We also investigated whether the oligoclonality of TIL was more significantly induced after definitive CRT, because radiation and chemotherapy have been previously reported to induce neoantigens by disrupting cancer cells [ 17 , 31 , 32 ]. Preferably, we could compare the clonality of TIL between stage-adjusted ESCCs with and without preceding definitive CRT directly; however, it is difficult to recruit patients with stage II or III ESCCs that did not have preceding neoadjuvant therapies in Japan.…”

“…Recent advances in molecular biology and tumor immunology have revealed the fact that the therapeutic effects of chemotherapy or radiation should be greatly influenced by the tumor immunologic microenvironment [ 14 , 15 , 16 , 17 ]. Actually, many studies have suggested that the factors relating to the tumor microenvironment (TME), such as PD-L1 expression or the presence of tumor-infiltrating lymphocytes (TIL), could be prognostic or predictive marker candidates for chemotherapy or chemoradiation in various types of human cancers, including ESCC [ 18 , 19 , 20 , 21 , 22 , 23 ].…”

Exploiting Radiation Therapy to Restore Immune Reactivity of Glioblastoma

“…Other major immunogenic features of RT is to shape the T cell receptor (TCR) repertoire of TILs (108)(109)(110)(111)(112) and to expose immunogenic mutations to the immune system (113). A detailed discussion describing the mechanisms responsible for the increase of antigenicity in irradiated tumors can be found elsewhere (114).…”

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…Emerging combinations also include ICIs associated with radiotherapy [136]. Radiotherapy remodels intratumoral T cell responses and supports refined sequencing of combination strategies in RCC [183]. The specific observations of T cell expansion and contraction within distinct time points of observation offer a rationale for the timing of combination strategies that leverage endogenous T cell responses to improve patient outcomes [183].…”

“…Radiotherapy remodels intratumoral T cell responses and supports refined sequencing of combination strategies in RCC [183]. The specific observations of T cell expansion and contraction within distinct time points of observation offer a rationale for the timing of combination strategies that leverage endogenous T cell responses to improve patient outcomes [183]. RCC patients treated with SBRT exhibit broad transcriptional immune activation and increased clonality, with an underlying heightened proportion of dominant motifs [183].…”