TY - JOUR 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 DO - 10.1136/jitc-2020-002256 VL - 9 IS - 7 SP - e002256 AU - Elodie Lauret Marie Joseph AU - Amos Kirilovsky AU - Benoît Lecoester AU - Carine El Sissy AU - Laura Boullerot AU - Laurie Rangan AU - Amélie Marguier AU - Florent Tochet AU - Magalie Dosset AU - Jihane Boustani AU - Patrice Ravel AU - Romain Boidot AU - Laurie Spehner AU - Nacilla Haicheur-Adjouri AU - Florence Marliot AU - Jean-René Pallandre AU - Francis Bonnefoy AU - Viorel Scripcariu AU - Marc Van den Eynde AU - Emmanuel Cornillot AU - Céline Mirjolet AU - Franck Pages AU - Olivier Adotevi Y1 - 2021/07/01 UR - http://jitc.bmj.com/content/9/7/e002256.abstract N2 - 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. ER -