1. Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy
- Author
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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, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Service de gastro-entérologie, and UCL - (SLuc) Unité d'oncologie médicale
- Subjects
Cancer Research ,Immunology ,Mice ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,Immune Checkpoint Inhibitors ,radiotherapy ,RC254-282 ,Pharmacology ,combination ,Immunity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Basic Tumor Immunology ,adaptive immunity ,Chemoradiotherapy ,Th1 Cells ,drug therapy ,Disease Models, Animal ,Oncology ,Molecular Medicine ,Female ,Immunotherapy - 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.
- Published
- 2021