Uncovering the spatial landscape of molecular interactions within the tumor microenvironment through latent spaces

Recent advances in spatial transcriptomics (ST) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor and its microenvironment (TME). The direct characterization of cellular co-localization with spatial technologies facilities quantification of the molecular changes resulting from direct cell-cell interaction, as occurs in tumor-immune interactions. We present SpaceMarkers, a novel bioinformatics algorithm to infer molecular changes from cell-cell interaction from latent space analysis of ST data. We apply this approach to infer molecular changes from tumor-immune interactions in Visium spatial transcriptomics data of metastasis, invasive and precursor lesions, and immunotherapy treatment. Further transfer learning in matched scRNA-seq data enabled further quantification of the specific cell types in which SpaceMarkers are enriched. Altogether, SpaceMarkers can identify the location and context-specific molecular interactions within the TME from ST data. ### Competing Interest Statement EJF is on the Scientific Advisory Board of Viosera Therapeutics and is a paid consultant for Merck and Mestag Therapeutics. WJH reports royalties from Rodeo/Amgen; grants from Sanofi and NeoTX; and consulting fees from Exelixis outside the submitted work. EMJ reports other support from Abmeta, personal fees from Genocea, personal fees from Achilles, personal fees from DragonFly, other support from Parker Institute, grants and other support from Lustgarten, personal fees from Carta, grants and other support from Genentech, grants and other support from AstroZeneca, personal fees from NextCure, and grants and other support from Break Through Cancer. SRW, CRU, JC, AH, and ZWB are equity stockholders and employees of 10x Genomics. LZ receives grant support from Bristol-Meyer Squibb, Merck, AstraZeneca, iTeos, Amgen, NovaRock, Inxmed, and Halozyme. LZ is a paid consultant/Advisory Board Member at Biosion, Alphamab, NovaRock, Ambrx, Akrevia/Xilio, QED, Natera, Novagenesis, Snow Lake Captials, Tempus, Amberston, and Mingruizhiyao. LZ holds shares at Alphamab and Mingruizhiyao. MY reports grants and research support from: Bristol-Myers Squibb, Incyte, Genentech, and honoraria from Genentech, Exelixis, Eisai, AstraZeneca, Replimune, Hepion. CSM reports research funding from Pfizer, Astrazeneca, BMS, GSK/Tesaro, and serves on the advisory boards of Bristol Myers Squibb (not paid), Seattle Genetics, Genomic Health, Athenex. RAA receives research support from Bristol Myers Squibb, RAPT therapeutics, Stand up to Cancer, and the National Institutes of Health and serves on the advisory boards for Bristol Myers Squibb, Merck SD, and AstraZeneca. ASP is a consultant to AsclepiX Therapeutics and CytomX Therapeutics; he is the founder and Chief Scientific Advisor of AsclepiX Therapeutics; he receives research grants from AstraZeneca and Boehringer Ingelheim. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.