| Autor: |
George Coukos, Melita Irving, Denarda Dangaj Laniti, Santiago J. Carmona, Lana E. Kandalaft, Alexandre Harari, Urania Dafni, Christine Sempoux, Stefan Zimmermann, Mikaël J. Pittet, Sylvie Rusakiewicz, Periklis Foukas, Sarah E. Warren, Thomas Smith, Marius Messemaker, Zoi Tsourti, Georgia Dimopoulou, Jean Bourhis, Niklaus Schaefer, John Prior, Clarisse Dromain, Rafael Duran, Khalil Zaman, Apostolos Sarivalasis, Dominik R. Berthold, Blanca Navarro Rodrigo, Eleonora Ghisoni, Martina Imbimbo, Angela Orcurto, Raphael Genolet, Fabrizio Benedetti, Aodrenn Spill, Jesus Corria-Osorio, Massimo Andreatta, Isaac Crespo, David Barras, Maria Ochoa de Olza, Catherine Ronet, Fernanda G. Herrera |
| Rok vydání: |
2023 |
| DOI: |
10.1158/2159-8290.c.6549407.v1 |
| Popis: |
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell–infiltrated tumors.Significance:Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1 |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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