151. Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells.
- Author
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Alissafi T, Hatzioannou A, Mintzas K, Barouni RM, Banos A, Sormendi S, Polyzos A, Xilouri M, Wielockx B, Gogas H, and Verginis P
- Subjects
- Animals, 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 pathology, Neoplasms pathology, Tumor Microenvironment immunology, Autophagy immunology, Myeloid-Derived Suppressor Cells immunology, Neoplasms immunology, Neoplasms therapy
- 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.
- Published
- 2018
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