Abstract
Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.
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Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request. The METABRIC patient dataset can be publicly accessed via cBioPortal at https://www.cbioportal.org/study/summary?id=brca_metabric. The Molecular Signature Database is publicly available at https://www.gsea-msigdb.org/gsea/msigdb/index.jsp. Source data are provided with this paper.
Code availability
The code employed for in silico studies has been deposited at GitHub and is publicly available at https://github.com/icbi-lab/Yamazaki_et_al_Nature_Immunology_2020. Source data are provided with this paper.
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Acknowledgements
The authors are indebted to B. Vogelstein (Johns Hopkins University) for sharing BAX+/− and BAX−/− HCT 116 cells and the WCM Radiation Biology Core Facility (in particular J. Kraynak) for help with irradiation procedures. F.F. is supported by the Austrian Science Fund (FWF) (project no. T 974-B30). E.N.M. is supported by an FPU fellowship from Ministerio de Educación Cultura y Deporte of Spain (FPU16/06537). S.C.F. is supported by Breakthrough Level 2 and 3 grants from the US Department of Defense Breast Cancer Research Program (BC180476, PI: Formenti; BC180595, PI: Formenti, Demaria) and by an S10 Instrumentation Grant from National Institutes of Health (RR027619-01). The L.G. laboratory is supported by a Breakthrough Level 2 grant from the US Department of Defense Breast Cancer Research Program (BC180476P1, PI: Galluzzi), by the 2019 Laura Ziskin Prize in Translational Research (ZP-6177, PI: Formenti) from Stand Up to Cancer, by a Mantle Cell Lymphoma Research Initiative (PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society, by a startup grant from the Department of Radiation Oncology at Weill Cornell Medicine, by a Rapid Response Grant from the Functional Genomics Initiative, by industrial collaborations with Lytix Biopharma and Phosplatin Therapeutics and by donations from Phosplatin, the Luke Heller TECPR2 Foundation and Sotio a.s.
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Contributions
T.Y. performed the majority of experimental assessments with the help of A.S. and M.R. and prepared figures with the help of A.B. and NB. A.B., G.P., N.B. and L.S. provided additional experimental support. A.B. performed automated image analyses. A.K. performed in silico analyses with support from F.F. and under supervision by Z.T. E.N.M. performed qPCR on patient samples. F.A.P. and E.G.M. identified patient samples and performed statistical analyses on patient data with support from A.K. S.C.F. provided infrastructure and clinical input on the project. L.G. conceived the project, directed experimental and biostatistical assessments, interpreted data, wrote the manuscript and supervised figure preparation. All authors approved the final version of the paper.
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F.A.P. declares research funding from Celgene and Roche and speaker and/or advisory honoraria from Pfizer, Roche, AstraZeneca, Celgene, Eisai, Novartis, Pierre Fabre and Roche. E.G.M. declares research funding from Roche and speaker and/or advisory honoraria from AstraZeneca, Roche and Pharmamar. S.C.F. declares funding for clinical trials from Bristol Myers Squibb, Merck and Varian and speaker and/or advisory honoraria from Astra Zeneca, Bayer, Bristol Myers Squibb, Eisai, Elekta, EMD Serono/Merck, GlaxoSmithKline, Janssen, MedImmune, Merck US, Regeneron, Varian and ViewRay. L.G. declares research funding from Lytix Biopharma and Phosplatin Therapeutics and speaker and/or advisory honoraria from Boehringer Ingelheim, Astra Zeneca, OmniSEQ, the Longevity Labs, Inzen and the Luke Heller TECPR2 Foundation.
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Extended data
Extended Data Fig. 1 Autophagy supports radioresistance in vitro and in vivo.
a, Protein levels of unconjugated ATG5, ATG5-ATG12 conjugates, and ATG7 in control (SCR) and Atg5–/– or Atg7–/– TS/A cell clones generated for the purpose of this study, as determined by immunoblotting. ACTB levels were monitored to ensure equal lane loading. b, Percentage of TS/A cells preserving plasma membrane integrity, as assessed by the vital dye propidium iodide (PI), 24 h after exposure to the γ irradiation (4 Gy) in the optional presence of 25 µM hydroxychloroquine (HCQ). Results are means ± SEM and individual data points. Number of biologically independent samples collected over 5 (Control, 4 Gy) or two (HCQ, HCQ + 4 Gy) independent experiments and p values (one way-ANOVA plus Fisher LSD as compared to untreated TS/A cells*, unpaired two-sided Student’s t test as compared to irradiated TS/A cells#) are reported. c, Tumor growth (individual curves) and overall survival (OS) of immunocompetent BALB/c mice implanted with SCR, Atg5–/– and Atg7–/– TS/A cells and optionally treated with intraperitoneal mitoxantrone (MTX). Number of animals and p values (two-sided log-rank as compared to untreated mice bearing lesions of the same genotype) are reported. d, Percentage of tumor-free BALB/c mice upon challenge with a tumorigenic number of living SCR TS/A cells 2 weeks days after vaccination with PBS (negative control) or TS/A cells of the indicated genotype pre-cultured for 24 h with 1 µM MTX. Number of animals, tumor-free survival (TFS) at the end of the experiment, and p values (two-sided log-rank as compared to PBS vaccination* or vaccination with irradiated SCR cells#) are reported.
Extended Data Fig. 2 Autophagy inhibits type I IFN secretion by irradiated cancer cells as a consequence of improved cytosolic DNA clearance.
a-d, Ifnb1 (a, c) or secreted type I IFN (b, d) levels in control (SCR) or Atg7–/– mouse mammary carcinoma EO771 cells (a, b), wild-type mouse fibrosarcoma MCA205 cells (c), and wild-type human mammary carcinoma MCF7 cells (d), optionally exposed to γ irradiation (8 Gy) and cultured in control conditions or in the presence of 10–25 µM hydroxychloroquine (HCQ) for 24 h, as assessed by RT-PCR (a, c) or ELISA (b, d). Results are means ± SEM and individual data points. Number of biologically independent samples collected over three (a, c, d) or two (b) independent experiments and p values (one way-ANOVA plus Fisher LSD as compared to untreated SCR cells*, unpaired two-sided Student’s t test as compared to irradiated wild-type or SCR cells#) are reported. n.d., not detectable above blank. ATG7 levels and ATG5 conjugation status as assessed by immunoblotting are depicted. ACTB levels were monitored to ensure equal lane loading. e, Ifnb1 levels in Atg7–/– TS/A cells optionally exposed to γ irradiation (8 Gy) and then cultured in control conditions or in the presence of 10 µM RU320521 (RU.521) for 48 h, as assessed by quantitative RT-PCR. Results are means ± SEM and individual data points. Number of biologically independent samples and p values (paired two-sided Student’s t test as compared to irradiated Atg7–/– cells#) are reported.
Extended Data Fig. 3 Autophagy inhibits type I IFN secretion by limiting cytosolic mtDNA accumulation.
a, Micronucleation in wild-type TS/A cells optionally exposed to γ irradiation at the indicated dose (8 Gy) and maintained in control conditions for 24 h. Representative images (scale bar = 30 µm) and quantitative data are reported. Results are means ± SEM and individual data points. Number of images from biologically independent samples collected over three independent experiments and p value (unpaired two-sided Student’s t test as compared to untreated cells*) are reported. b, Cytosolic dsDNA species in rho0 TS/A cells exposed to γ irradiation at the indicated dose (8 Gy) and maintained in control conditions for 24 h, as assessed by high resolution confocal microscopy upon immunofluorescence staining with antibodies specific for dsDNA and COX4. DAPI was employed as nuclear counterstain. Representative images (scale bar = 20 μm) are reported from a total of 9 (control) and 13 (8 Gy) collected from biologically independent samples over three independent experiments. c. COX4 levels in wild-type and rho0 TS/A cells, as assessed by immunoblotting with COX4-specific antibodies. ACTB levels were assessed to ensure equal lane loading. d, BCL2 levels in wild-type TS/A cells and TS/A cells transiently transfected with a commercial plasmid for BCL2-overexpression (BCL2++), as assessed by immunoblotting with BCL2-specific antibodies. ACTB levels were assessed to ensure equal lane loading. e, f, Amount of cytosolic dsDNA in wild-type and BCL2-overexpressing (BCL2++) TS/A cells (e) or BAX+/– and BAX–/– human colorectal carcinoma HCT 116 cells (f) optionally exposed to γ irradiation (8 Gy, e; 20 Gy, f) and cultured in control conditions for 48 h, as assessed by conventional immunofluorescence microscopy and automated image analysis. DAPI was employed as nuclear counterstain. Representative images (scale bar = 20 μm) from a total of 17 (e, wild-type TS/A cells), 18 (e, BCL2++ TS/A cells), 10 (f, BAX+/– HCT 116 cells) and 18 (f, BAX–/– HCT 116 cells) collected from biologically independent samples over three independent experiments. g. Mitochondrial (mt) and genomic (g) DNA levels in control (SCR), Atg5–/– and Atg7–/– TS/A cells maintained in control conditions or subjected to mtDNA depletion by long-term exposure to ethidium bromide (rho0), as assessed by quantitative PCR with specific primers. Densitometry upon normalization to gDNA is reported.
Extended Data Fig. 4 Impact of autophagic proficiency and mtDNA levels on clinical breast cancer outcome.
a, b, Unsupervised hierarchical clustering of top 400 differentially expressed genes (DEGs) in 1351 breast cancer patients from the METABRIC database for whom cancer-specific overall survival (CSOS) data are available, upon median stratification of a gene signature based on the z-scored median expression of ATG5, ATG7, ATG10, ATG12 and ATG16L1 (ATG signature). Gene set enrichment analysis (GSEA) for the GO terms “response to type I interferon” and “response to interferon gamma”, as well as for the Hallmarks (HL) terms “interferon alpha response” and “interferon gamma response” is depicted. Normalized enrichment scores (NES) and false discovery rate (FDR)-adjusted p values (q values as calculated in the GSEA analysis) are reported. c, GSEA for the GO term “response to gamma radiation” in all 1820 breast cancer patients from the METABRIC database, as well as in 1351 patients for whom CSOS information is available upon median stratification based on the ATG signature. NES and FDR-adjusted p values (q values as calculated in the GSEA analysis) are reported. d, Intensity of a genetic signature representative of mitochondrial abundance (Mitoonly) in the tumor microenvironment of 1820 unselected breast cancer patients from the METABRIC database stratification by median, tertiles or quartiles of the ATG signature. p values (Kruskal Wallis) are reported. Boxplots represent median, upper and lower quartiles, and additional points within 1.5 times the interquartile range from upper or lower quartiles. e, Disease-free survival (DFS) and overall survival (OS) of 37 breast cancer patients from the University Hospital of Murcia for which bioptic material from the primary tumor was available, upon median stratification based on mitochondrial (mt) to genomic (g) DNA ratio. p values (two-sided log-rank) are reported. See also Extended Data Table 3. f, DFS of 9 breast cancer patients from the University Hospital of Murcia for which bioptic material from metastatic lesions at relapse or progressive disease was available, upon median stratification based on mitochondrial (mt) to genomic (g) DNA ratio. p values (two-sided log-rank) are reported.
Supplementary information
Supplementary Information
Supplementary Figs. 1 and 2.
Supplementary Video 1
Z-stack reconstruction of wild-type TS/A cells maintained in control conditions then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and LMNB-specific (green) antibodies. See also Fig. 3a.
Supplementary Video 2
Z-stack reconstruction of wild-type TS/A cells exposed to γ irradiation (8 Gy) and cultured in control conditions for 24 h then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and LMNB-specific (green) antibodies. See also Fig. 3a.
Supplementary Video 3
Z-stack reconstruction of wild-type TS/A cells maintained in control then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and COX4-specific (green) antibodies. See also Fig. 3c.
Supplementary Video 4
Z-stack reconstruction of wild-type TS/A cells exposed to γ irradiation (8 Gy) and cultured in control conditions for 24 h then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and COX4-specific (green) antibodies. See also Fig. 3c.
Supplementary Video 5
Z-stack reconstruction of wild-type TS/A cells maintained in control conditions then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and TFAM-specific (green) antibodies. See also Fig. 3e.
Supplementary Video 6
Z-stack reconstruction of wild-type TS/A cells exposed to γ irradiation (8 Gy) and cultured in control conditions for 24 h then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and TFAM-specific (green) antibodies. See also Fig. 3e.
Supplementary Video 7
Z-stack reconstruction of mtDNA-depleted TS/A cells maintained in control conditions then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and LMNB-specific (green) antibodies. See also Fig. 4c.
Supplementary Video 8
Z-stack reconstruction of mtDNA-depleted TS/A cells exposed to γ irradiation (8 Gy) and cultured in control conditions for 24 h then stained with DAPI (nuclear counterstain) plus dsDNA-specific (red) and LMNB-specific (green) antibodies. See also Fig. 4c.
Supplementary Table 1
Differential gene expression analysis on the METABRIC cohort and survival analysis on the METABRIC and Murcia cohort.
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Source Data Extended Data Fig. 1
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Unprocessed western blots.
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Yamazaki, T., Kirchmair, A., Sato, A. et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat Immunol 21, 1160–1171 (2020). https://doi.org/10.1038/s41590-020-0751-0
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DOI: https://doi.org/10.1038/s41590-020-0751-0
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