Abstract PR019: Integrative multi-omic profiling reveals immune microenvironment subtypes in renal cell carcinoma

Abstract Renal cell carcinoma (RCC) is characterized by extensive but heterogeneous immune infiltration. Although RCC responds to immune checkpoint inhibitors, only a subset of patients derives durable benefit, underscoring gaps in our understanding of the tumor immune microenvironment (TIME) and mechanisms of immune evasion. Here, we integrated single-cell and spatial profiling to identify conserved TIMEs and uncover key biological differences with potential relevance for precision therapy. Single-cell RNA and matched TCR-seq (scRNA/TCR-seq) were performed on fresh surgical samples collected through the REMEDY study at the University Health Network (Toronto, Canada). Imaging mass cytometry (IMC) was conducted on spatially matched tumor regions from 54 patients. High-resolution immune, stromal, and malignant states identified by scRNA-seq guided the design of a tailored IMC antibody panel, enabling integration of datasets and definition of reproducible spatial architectures of the RCC TIME. We identified seven high-resolution patient immunophenotypes, including a vascular-dense subtype and several highly immune-infiltrated subtypes characterized by myeloid-dominant, immunosuppressive and pro-inflammatory microenvironments. Representative gene signatures derived using a linear mixed model were applied to publicly available bulk RNA-seq datasets (TCGA, JAVELIN, IMmotion151), revealing subtype-specific associations with survival and immunotherapy (IO) outcomes in univariate analyses. Comparisons of clonal expansion and T-cell differentiation across subtypes showed distinct patterns that highlight potential mechanisms for their differing capacities to respond to IO. Subtype differences were also evident in TAM programs, with immunosuppressive macrophage states (SPP1+, CD163+ TAMs) likely contributing to the suppressive immunophenotype and CXCL9+ TAMs supporting more pro-inflammatory contexts. Spatially informed pathway and cell-cell interaction analyses further delineated subtype-specific functional programs, including regulatory NK-tumour interactions enriched in the immunosuppressive subtype. Overall, this study identifies conserved immunophenotypes that relate to differential survival and IO responsiveness in RCC and provides a resource dataset to support ongoing efforts to develop precision immunotherapy approaches against this disease. Citation Format: Shirley Hui, Jennifer Pfeil, Daniel Stueckmann, Xiaoyu Zhang, Lisa Martin, Maria Komisarenko, Jalna Meens, Jennifer Gorman, Julia Szusz, Stephane Chevrier, Sujana Sivapatham, Somi Afiuni, Philip Jonsson, Fred Davis, Cristina Penaranda, Susan Prendeville, Laurie Ailles, Bernd Bodenmiller, Nicolas Stransky, Gromoslaw Smolen, Gary D. Bader, Antonio Finelli, Hartland Jackson, Keith Lawson. Integrative multi-omic profiling reveals immune microenvironment subtypes in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr PR019.