Adding liposomal doxorubicin enhances the abscopal effect induced by radiation/αPD1 therapy depending on tumor cell mitochondrial DNA and cGAS/STING.

Autor:	Wang L; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany.; Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, China., Luo R; Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, China luorenbu@gmail.com gabriele.niedermann@uniklinik-freiburg.de.; Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.; Faculty of Biology, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Onyshchenko K; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany.; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Rao X; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany.; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Wang M; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany., Menz B; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany., Gaedicke S; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany., Grosu AL; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany.; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany., Firat E; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany., Niedermann G; Department of Radiation Oncology, University of Freiburg Faculty of Medicine, Freiburg, Germany luorenbu@gmail.com gabriele.niedermann@uniklinik-freiburg.de.; German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany.; German Cancer Research Center (DKFZ), Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Aug; Vol. 11 (8).
DOI:	10.1136/jitc-2022-006235
Abstrakt:	Background: Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade. However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT/αPD-1 and Doxil/αPD-1. We also investigated whether the enhanced abscopal responses depended on the mitochondrial DNA (mtDNA)/cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)/IFN-I pathway. Materials/methods: We used Doxil in combination with RT and αPD-1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Mechanistic studies on the role of the mtDNA/cGAS/STING/IFN-I axis were performed using inhibitors and knockout cells in vitro as well as in mice. Results: Addition of a single low dose of Doxil to RT and αPD-1 strongly enhanced the RT/αPD-1-induced abscopal effect in both models. Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and more tumor-specific CD8 + T cells than RT/αPD-1 and Doxil/αPD-1, particularly in non-irradiated tumors. Coincubation of Doxil-treated and/or RT-treated tumor cells with DCs enhanced DC antigen cross-presentation which is crucial for inducing CD8 + T cells. CD8 + T cell depletion or implantation of cGAS-deficient or STING-deficient tumor cells abolished the abscopal effect. Doxorubicin-induced/Doxil-induced IFNβ1 markedly depended on the cGAS/STING pathway. Doxorubicin-treated/Doxil-treated tumor cells depleted of mtDNA secreted less IFNβ1, of the related T cell-recruiting chemokine CXCL10, and ATP; coincubation with mtDNA-depleted tumor cells strongly reduced IFNβ1 secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated/abscopal site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8 + T cells. Conclusions: These data show that single low-dose Doxil can substantially enhance the RT/αPD-1-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8 + tumor-specific T cells particularly in abscopal tumors compared with RT/αPD-1 and Doxil/αPD-1. Moreover, they indicate that the mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic/immunomodulatory doxorubicin effects. Our findings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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