Radiation-Induced Immunity in Kidney Cancer Patients: Seq-ing Commonality Between Peripheral and Intratumoral T cell Repertoires

Abstract

Abstract Radiation has long been part of the standard of care for cancer treatment. Clinical studies combining immunotherapy with radiation have shown promising response rates implicating radiotherapy as an inducer of tumor immunity. Due to the scarcity of human samples treated in situ with radiation, exploration of this phenomenon has been largely limited to murine models. While these data draw connections between intratumoral immune responses and wider effects in peripheral blood, advances in patient care are restricted by inherent differences between murine models and human disease. Therefore, to identify commonality between local intratumoral and systemic responses to radiation, we analyzed clinical trial samples from renal cell carcinoma (RCC) patients treated with stereotactic body radiation therapy (SBRT) at the primary tumor. With access to patient tumors and peripheral blood, we hypothesized that SBRT initiates local and systemic anti-tumor immunity. Pathway analysis from tumor RNAseq data showed SBRT-specific immune processes: TCR activation, increased costimulation, and chemokine signaling. Deeper examination through single cell RNA sequencing identified the sources of these signals. In parallel, analysis by T cell receptor sequencing (TCRseq) showed increased tumor T cell clonality with SBRT treatment. TCRseq of serial blood samples revealed tumor-enriched T cell clonotypes reaching peak abundance 2 weeks post-SBRT. This expansion was not sustained and contracted towards baseline levels 4 weeks after SBRT. Collectively, these results indicate a critical interval following radiation, wherein tumor-enriched T cell clones are expanded in circulation, that could be utilized to bolster responses to immunotherapy.