RRC ID 53175
Author Alissafi T, Hatzioannou A, Mintzas K, Barouni RM, Banos A, Sormendi S, Polyzos A, Xilouri M, Wielockx B, Gogas H, Verginis P.
Title Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells.
Journal J Clin Invest
Abstract Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune responses. Notably, tumor-infiltrating autophagy-deficient monocytic MDSCs (M-MDSCs) demonstrated impaired suppressive activity in vitro and in vivo, whereas transcriptome analysis revealed substantial differences in genes related to lysosomal function. Accordingly, autophagy-deficient M-MDSCs exhibited impaired lysosomal degradation, thereby enhancing surface expression of MHC class II molecules, resulting in efficient activation of tumor-specific CD4+ T cells. Finally, targeting of the membrane-associated RING-CH1 (MARCH1) E3 ubiquitin ligase that mediates the lysosomal degradation of MHC II in M-MDSCs attenuated their suppressive function, and resulted in markedly decreased tumor volume followed by development of a robust antitumor immunity. Collectively, these findings depict autophagy as a molecular target of MDSC-mediated suppression of antitumor immunity.
Volume 128(9)
Pages 3840-3852
Published 2018-8-31
DOI 10.1172/JCI120888
PII 120888
PMID 29920188
PMC PMC6118632
MeSH Animals Autophagy / immunology* Autophagy-Related Protein 5 / deficiency Autophagy-Related Protein 5 / genetics Autophagy-Related Protein 5 / immunology CD4-Positive T-Lymphocytes / immunology CD4-Positive T-Lymphocytes / pathology Cell Differentiation / immunology Cell Line, Tumor Female Histocompatibility Antigens Class II / metabolism Humans Immune Tolerance Immunotherapy Lymphocyte Activation Lymphocytes, Tumor-Infiltrating / immunology Lymphocytes, Tumor-Infiltrating / pathology Lysosomes / immunology Lysosomes / metabolism Melanoma / immunology Melanoma / pathology Melanoma / therapy Melanoma, Experimental / immunology Melanoma, Experimental / pathology Melanoma, Experimental / therapy Mice Mice, Inbred C57BL Mice, Transgenic Myeloid-Derived Suppressor Cells / immunology* Myeloid-Derived Suppressor Cells / pathology Neoplasms / immunology* Neoplasms / pathology Neoplasms / therapy* Tumor Microenvironment / immunology
IF 11.864
Times Cited 10
Mice RBRC02975