Abstract 4991: Radiotherapy-induced immunological and therapeutic response depends on stem-like TCF-1+PD-1+CD8+ T-cells

Abstract

Abstract Radiotherapy is a frequently used treatment for cancer. Recent data, including ours, showed that radiotherapy promotes an inflammatory response in the tumor that supports tumor-specific immunity, and in fact, the efficacy of radiotherapy in pre-clinical models depends on CD8+ T-cells. According to our preliminary data, the response to radiotherapy is independent of de novo recruited CD8+ T-cells, suggesting that radiation drives differentiation and proliferation of preexisting intratumoral CD8+ T-cells. Intratumoral CD8+ T-cells are heterogeneous concerning phenotype and function. Under conditions of chronic stimulation by antigen, a subset of CD8+ T-cells expressing PD-1 and the transcription factor TCF-1 was described. These so-called stem-like CD8+ T-cells, which give rise to effector cells, were shown to be essential for the clinical response to PD-1 blockade. How radiotherapy influences the different CD8+ T-cell subsets in the tumor microenvironment has not been comprehensively investigated. We propose that the efficacy of radiotherapy depends on the presence of stem-like CD8+ T-cells, presumably by giving rise to effector cells. To address this, we selectively depleted TCF-1+ cells from tumor-bearing mice immediately before radiotherapy. Subsequently, we correlated tumor regression with the immunological response using single-cell analyses of intratumoral CD8+ T-cells. In the absence of TCF-1+ cells, we found a reduced efficacy and reduced number of intratumoral effector cells after radiotherapy. We currently analyze our single-cell RNA-sequencing data and expect to discover novel radiotherapy-induced pathways in CD8+ T-cells that contribute to therapeutic efficacy. Citation Format: Hakan Köksal, Michael Herbst, Nicola Marti, Maries van den Broek. Radiotherapy-induced immunological and therapeutic response depends on stem-like TCF-1+PD-1+CD8+ T-cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4991.