RT Journal Article SR Electronic T1 Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e002256 DO 10.1136/jitc-2020-002256 VO 9 IS 7 A1 Elodie Lauret Marie Joseph A1 Amos Kirilovsky A1 Benoît Lecoester A1 Carine El Sissy A1 Laura Boullerot A1 Laurie Rangan A1 Amélie Marguier A1 Florent Tochet A1 Magalie Dosset A1 Jihane Boustani A1 Patrice Ravel A1 Romain Boidot A1 Laurie Spehner A1 Nacilla Haicheur-Adjouri A1 Florence Marliot A1 Jean-René Pallandre A1 Francis Bonnefoy A1 Viorel Scripcariu A1 Marc Van den Eynde A1 Emmanuel Cornillot A1 Céline Mirjolet A1 Franck Pages A1 Olivier Adotevi YR 2021 UL http://jitc.bmj.com/content/9/7/e002256.abstract AB Background Multiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.Methods This study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining.Results Front-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity.Conclusions Our results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.Data are available upon reasonable request. RNAseq data from mouse tumor exposed to chemoradiotherapy is available in a public two years following the publication.