Integrated single-cell and spatial transcriptomic analyses unravel the heterogeneity of the prostate tumor microenvironment

The treatment of primary prostate cancer delicately balances an active surveillance approach for low-risk disease with multimodal treatment including surgery, radiation therapy, and hormonal therapy for high-risk disease. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we sought to comprehensively describe the tumor microenvironment of localized prostate cancer contrasting this with adjacent normal samples and healthy controls. We performed single-cell RNA sequencing and high-resolution spatial transcriptomic analysis. This revealed tumor context dependent changes in gene expression. Our data point towards an immune suppressive tumor microenvironment associated with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We inferred cell-to-cell relationships at an unprecedented scale for ligand-receptor interactions within undissociated tissue sections. Our work provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions. Highlights ### Competing Interest Statement A.O.S. own shares in TScan Therapeutics and BioNTech. P.V.K. serves on the Scientific Advisory Board to Celsius Therapeutics Inc. and Biomage Inc. P.V.K. consults National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation. D.T.S. is a founder, director and stockholder of Magenta Therapeutics, Clear Creek Bio, and LifeVaultBio. He is a director and stockholder of Agios Pharmaceuticals and Editas Medicines and a founder and stockholder of Fate Therapeutics and Geruda Therapeutics. He is a consultant for FOG Pharma, Inzen Therapeutics, ResoluteBio and VCanBio and receives sponsored research support on an unrelated project from Sumitomo Dianippon. D.B.S. is a founder, consultant and shareholder for Clear Creek Bio. K.S. is a recipient of sponsored research funding from Convergent Genomics. F.C. and E.Z.M. are consultants for Atlas Bio, inc.