guest ::
| Home > Publications database > Doxorubicin Enhances the Abscopal Effect Depending on Tumor Cell Mitochondrial DNA and cGAS/STING. |
| Home > Publications database > Doxorubicin Enhances the Abscopal Effect Depending on Tumor Cell Mitochondrial DNA and cGAS/STING. |
| Journal Article | DKFZ-2023-01990 |
; ; ;
2023
Elsevier Science
Amsterdam [u.a.]
Abstract: Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). 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+ICB, Doxil+ICB, or RT+Doxil.We used Doxil in combination with RT and αPD1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated.Triple therapy with RT, αPD1, and single low-dose Doxil strongly enhanced the RT-induced abscopal effect compared to all double and single treatments in both tumor models (p < 0.05, n = 5-10 mice/group). Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and tumor-specific CD8 T cells than RT/αPD1 and Doxil/αPD1 (p < 0.05, n = 5 mice/group), particularly in non-irradiated tumors. CD8 T cell depletion or implanting STING-deficient tumor cells abolished the abscopal effect. By using inhibitors and knockout cells, we show that doxorubicin/Doxil-induced IFNβ1 markedly depended on the cGAS/STING pathway (p < 0.05) which drives antitumor CD8 T cell responses through cross-presenting DCs. In mitochondrial DNA (mtDNA)-depleted tumor cells, doxorubicin/Doxil induced less IFNβ1 (p < 0.05), the related T cell-recruiting chemokine CXCL10 (p < 0.0001), and ATP (p < 0.0001); coincubation with mtDNA-depleted tumor cells strongly reduced IFNβ1 (p < 0.01) secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8 T cells (p < 0.05).Single low-dose Doxil can substantially enhance the RT-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8 tumor-specific T cells particularly in abscopal tumors compared with RT/αPD1 and Doxil/αPD1. The mtDNA/cGAS/STING/IFN-I axis is important for the immunogenic doxorubicin effects. Our findings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz
; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection
|
The record appears in these collections: |