VPS72 Controls Regulatory T Cell Adaptation and Stability in the Tumor Microenvironment 3961

Abstract Description The tumor microenvironment (TME) factors promote regulatory T cells (Treg) stability and function, but detailed epigenetic mechanisms for this regulation remain unclear. The vacuolar protein sorting-associated protein 72 homolog (VPS72), a H2A.Z chaperon protein, is highly expressed in various tumors and positively correlated with tumor progression, and TME Treg from cancer patients expressed significantly higher VPS72 than peripheral blood Tregs. To investigate the role of VPS72 in TME Treg regulation, we generated Treg-specific (VPS72-TregKO) and inducible (VPS72-TregiKO) VPS72 KO mice. In VPS72-TregKO mice, peripheral Tregs differentiation and function were severely interrupted, leading to lethal multi-organ autoimmune diseases. Bulk RNA-seq analysis confirmed the critical roles of VPS72 in Treg differentiation, homeostasis, and function. In the B16 melanoma model, VPS72-TregiKO mice exhibited significantly reduced tumor growth and progression. scRNA-seq analysis of the TME immune landscape revealed increased cytotoxic T infiltration, decreased MDSCs, enhanced T cell anti-tumor activities, and elevated DC antigen presentation and immunogenicity in VPS72-TregiKO mice. Overall, VPS72 play an essential role in Treg stability and functionality in the TME, making it a potential novel target for cancer immunotherapy. Detailed TME factors and epigenetic mechanisms on VPS72 mediated Treg regulation are currently under investigation. Funding Sources NIH/NCI R01 CA284740-01 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)