Τίτλος:
Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2018 American Society for Clinical Investigation. All rights reserved.
Συγγραφείς:
Alissafi, T.
Hatzioannou, A.
Mintzas, K.
Barouni, R.M.
Banos, A.
Sormendi, S.
Polyzos, A.
Xilouri, M.
Wielockx, B.
Gogas, H.
Verginis, P.
Περιοδικό:
JOURNAL OF CLINICAL INVESTIGATION
Εκδότης:
American Society for Clinical Investigation
Λέξεις-κλειδιά:
major histocompatibility antigen class 2; RING CH1 E3 ubiquitin ligase; small interfering RNA; transcriptome; ubiquitin protein ligase E3; unclassified drug; Atg5 protein, mouse; autophagy related protein 5; HLA antigen class 2, adoptive transfer; animal cell; animal experiment; animal model; animal tissue; antigen presentation; Article; autolysosome; autophagosome; autophagy; B16-F10 cell line; CD4+ T lymphocyte; controlled study; female; gene silencing; human; human cell; immune response; in vitro study; in vivo study; Lewis lung carcinoma cell line; melanoma; mouse; myeloid-derived suppressor cell; nonhuman; priority journal; protein degradation; T lymphocyte activation; transcriptomics; tumor associated leukocyte; tumor escape; tumor growth; tumor immunity; tumor immunogenicity; tumor volume; animal; autophagy; C57BL mouse; cell differentiation; experimental melanoma; genetics; immunological tolerance; immunology; immunotherapy; lymphocyte activation; lysosome; melanoma; metabolism; myeloid-derived suppressor cell; neoplasm; pathology; transgenic mouse; tumor associated leukocyte; tumor cell line; tumor microenvironment, Animals; Autophagy; Autophagy-Related Protein 5; CD4-Positive T-Lymphocytes; Cell Differentiation; Cell Line, Tumor; Female; Histocompatibility Antigens Class II; Humans; Immune Tolerance; Immunotherapy; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lysosomes; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Derived Suppressor Cells; Neoplasms; Tumor Microenvironment
