Stat3-mediated Atg7 expression regulates anti-tumor immunity in mouse melanoma

• DOI: 10.1007/s00262-024-03804-4
• Publication Date: 2024-09-05T09:05:12Z
• Authors: Sarah M. Zimmerman; Erin Suh; Sofia R. Smith; George P. Souroullas
• Keywords: STAT3 Transcription Factor; Brief Report; Melanoma, Experimental; CD8-Positive T-Lymphocytes; Autophagy-Related Protein 7; Epigenesis, Genetic; Mice, Inbred C57BL; Gene Expression Regulation, Neoplastic; Mice; Cell Line, Tumor; Tumor Microenvironment; Autophagy; Animals; Humans; Enhancer of Zeste Homolog 2 Protein; Melanoma

Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2Y641F interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by Ezh2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models, we further investigated the role of pathways downstream of Ezh2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of a wild-type or Ezh2Y641F epigenetic state. We found that the Atg7 locus is controlled by multiple Ezh2 and Stat3 binding sites, Atg7 expression is dependent on Stat3 expression, and that deletion of Atg7 slows down melanoma cell growth in vivo, but not in vitro. Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.