Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients
Menée à partir du séquençage de l'ARN d'échantillons tumoraux prélevés sur des patients atteints d'un carcinome à cellules rénales traité par radiothérapie corporelle stéréotaxique et menée à l'aide d'échantillons sanguins, cette étude met en évidence l'effet des rayonnements ionisants sur le répertoire des lymphocytes T
Strong evidence supports the tumor immune landscape as a determinant of patient responses to immunotherapy. Readily available therapies, including radiation, are being investigated as modifying agents with immune checkpoint blockade. However, little is known regarding radiotherapy’s impact within the tumor microenvironment and intratumoral T cell repertoires of patients, leaving critical gaps in the guided design of clinical protocols. In this study, samples from renal cell carcinoma (RCC) patients underwent high-throughput analysis to reveal transcriptional immune activation and increased clonality in irradiated tumors. Analysis across longitudinal blood samples showed that tumor-enriched clonotypes undergo phases of peripheral expansion and contraction following radiation. Collectively, these findings demonstrate that radiotherapy remodels intratumoral T cell responses and support refined sequencing of combination strategies in RCC.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.RNA-seq data have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE153262). Immunosequencing data can be accessed at the Adaptive Biotechnologies immuneACCESS site (https://clients.adaptivebiotech.com/pub/chow-2020-pnas).