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Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
Themis Alissafi, … , Helen Gogas, Panayotis Verginis
Themis Alissafi, … , Helen Gogas, Panayotis Verginis
Published June 19, 2018
Citation Information: J Clin Invest. 2018;128(9):3840-3852. https://doi.org/10.1172/JCI120888.
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Research Article Immunology

Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells

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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.

Authors

Themis Alissafi, Aikaterini Hatzioannou, Konstantinos Mintzas, Roza Maria Barouni, Aggelos Banos, Sundary Sormendi, Alexandros Polyzos, Maria Xilouri, Ben Wielockx, Helen Gogas, Panayotis Verginis

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Figure 6

Sustained IAb expression in autophagy-deficient tumor-derived M-MDSCs endows their immunogenic properties.

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Sustained IAb expression in autophagy-deficient tumor-derived M-MDSCs en...
(A) Representative flow cytometric analysis of CellTrace-labeled OTII CD4+ T cells cultured with M-MDSCs of Atg5ΔLysM and control B16-F10–inoculated mice in the presence of OVA peptide, n = 5 mice per group. (B) Gating strategy and frequencies of CD25+ (*P = 0.0236) and CD44+ (**P = 0.0116) OTII CD4+ T cells adoptively transferred in Atg5ΔLysM and control tumor-bearing mice, n = 3 mice per group. (C) Relative March1 expression in M-MDSCs following transfection with siRNA for March1 or scramble si (**P = 0.0006, n = 3 mice per group). (D) Representative histograms and MFI for IAb expression (*P = 0.0129) in M-MDSCs following transfection with siRNA for March1 or scramble si (n = 4 mice per group). For E and F, 4 × 105 M-MDSCs transfected with scramble si or si-March1 were s.c. coinjected with 3 × 105 B16-F10 cells in C57BL/6 mice (n = 7 mice per group). (E) Tumor volume (*P = 0.0044, **P = 0.017, ***P < 0.0001) and tumor weight (****P < 0.0001) are shown. (F) Numbers of CD45+ (**P = 0.0035), CD4+ (***P < 0.0001) and CD8+ (*P = 0.0307) T cells per 6 × 105 tumor cells are depicted. One representative experiment of 3 is shown. Results are mean ± SEM. Statistical significance was obtained by unpaired Student’s t test.
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