Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
Details
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State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_D82928F3BB2B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.
Journal
Cancer discovery
ISSN
2159-8290 (Electronic)
ISSN-L
2159-8274
Publication state
Published
Issued date
01/2022
Peer-reviewed
Oui
Volume
12
Number
1
Pages
108-133
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
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 <sup>+</sup> and CD8 <sup>+</sup> T cells. LDRT elicited predominantly CD4 <sup>+</sup> 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 <sup>+</sup> 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 <sup>+</sup> 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.
Pubmed
Web of science
Open Access
Yes
Create date
06/09/2021 7:16
Last modification date
29/04/2023 5:51