Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy.
J Immunother Cancer
; 9(7)2021 07.
Article
em En
| MEDLINE
| ID: mdl-34230108
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células Th1
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Quimiorradioterapia
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Inibidores de Checkpoint Imunológico
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Imunidade
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Imunoterapia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
França