Abstract 3015: HD-PTP mediates tumor suppression via modulation of anti-tumor immunity

Abstract The role of circulating extracellular vesicles in cancer biology is an area of intense research interest. Here, we reveal a tumor suppressor mechanism of HD-PTP (His Domain Protein Tyrosine Phosphatase, encoded by PTPN23), a protein associated with ESCRT (endosomal sorting complex required for transport), a complex that controls endosome sorting and exosome secretion. While loss of HD-PTP is known to be tumorigenic in mice and is frequently observed in human cancers including Triple Negative Breast Cancer (TNBC), the relevant pathways have remained obscure. We find that inhibition of HD-PTP in vivo promotes tumor progression selectively in a syngeneic, immune-competent TNBC model but not in a matched immune-deficient model. Through systematic profiling of the exosomal proteome in HD-PTP proficient and deficient cells, we identify PD-L1 as a key exosomal cargo selectively enriched due to loss of HD-PTP. Mechanistically, we show that inhibition of HD-PTP results in PD-L1 stabilization, its co-localization with the exosomal marker CD63, the enrichment of endosomal PD-L1 and subsequent increase in ExoPD-L1 release. Exosomes produced post HD-PTP loss inhibits antigen-dependent T cell activity in vitro, and HD-PTP inhibition in a syngeneic TNBC model promotes non-cell-autonomous, exosome- and PD-L1-dependent tumor progression, associated with reduced T cell infiltration and altered macrophage polarization. Consistent with these findings, low HD-PTP levels in human solid tumors are associated with decreased tumor infiltrating lymphocytes, poor response to immune checkpoint inhibition and inferior overall survival. Taken together, our studies unveil a novel tumor suppressor pathway controlling PD-L1 trafficking and ExoPD-L1 secretion, highlighting the critical roles of HD-PTP and ESCRT in anti-tumor immunity. Citation Format: Chenxu Guo, Sheng Sun, Nayana Thimmiah, Agustina Maccio, Siang Koh, Leif Ellisen. HD-PTP mediates tumor suppression via modulation of anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3015.