Loss of the Y chromosome evokes extrinsic extramedullary myelopoiesis via genome-wide epigenetic reprogramming of bladder cancer tumor cells 2255981

Abstract Introduction Loss of the Y chromosome (LOY) is a prevalent chromosomal alteration occurring in a substantial proportion of male patients with cancer including advanced bladder cancer (BLCA). Furthermore, LOY predicts reduced survival and terminal T cell exhaustion. However, the mechanisms underlying the profound immunological impacts of LOY remain unclear. Thus, the overarching rationale of this study is to define the tumor intrinsic and extrinsic drivers of immune reprogramming in LOY BLCA in order to develop targeted interventions. Methods Utilizing spectral flow cytometry, ATACseq, transcriptomic immunophenotyping, chemokine array profiling, adoptive cellular transfer and transgenic murine models we interrogated how LOY in cancer cells provokes immune dysfunction. Results Herein, we report that LOY in cancer cells provokes systemic, suppressive programming of monocyte derived macrophages via epigenetic derepression of aminopeptidase, ANPEP. Functionally, LOY induces loss of Y-encoded histone lysine demethylases KDM5D and UTY, culminating in a genome-wide shift in the epigenetic landscape of tumor cells. LOY or targeted deletion of KDM5D or UTY evoked ANPEP upregulation and ANPEP-driven accumulation of CCR2+ monocyte-derived macrophages via extramedullary myelopoiesis. Intercepting myeloid recruitment via CCR2 blockade, macrophage depletion or ANPEP ablation reduced LOY tumor growth. Inversely, enforced ANPEP expression in Y competent tumors promoted tumor progression, splenic expansion and macrophage accumulation. These findings highlight the protumor role of LOY and identify ANPEP/CCR2-axis signaling as therapeutic targets in BLCA while delineating a relationship between LOY and ANPEP in other solid tumors Conclusion Our results (1) elucidate the overarching role of the Y chromosome in shaping genome wide transcriptional accessibility via regulation of histone methylation and (2) substantiate how LOY coordinates profound immunological impacts in BLCA via chemokine-dependent myeloid reprogramming. Funding Source P01 CA278732/CA/NCI NIH HHS/United States Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)