Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy. Issue 7 (6th July 2021)

• Record Type: Journal Article
• Authors: Lauret Marie Joseph, Elodie; Kirilovsky, Amos; Lecoester, Benoît; El Sissy, Carine; Boullerot, Laura; Rangan, Laurie; Marguier, Amélie; Tochet, Florent; Dosset, Magalie; Boustani, Jihane; Ravel, Patrice; Boidot, Romain; Spehner, Laurie; Haicheur-Adjouri, Nacilla; Marliot, Florence; Pallandre, Jean-René; Bonnefoy, Francis; Scripcariu, Viorel; Van den Eynde, Marc; Cornillot, Emmanuel; Mirjolet, Céline; Pages, Franck; Adotevi, Olivier
• Is Part Of: Journal for immunotherapy of cancer. Volume 9:Issue 7(2021)
• Publication Date: 2021-07-06
• Subjects: tumor microenvironment -- drug therapy -- combination -- adaptive immunity -- immunotherapy -- radiotherapy; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-002256
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : 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.