PRJNA705464
Single cell sequencing links multiregional immune landscapes in clear cell renal cell carcinoma to tumor topology and therapy response
Clear cell renal cell carcinomas are highly immune infiltrated and can exhibit durable responses to immune checkpoint blockade. However, the extent of immune heterogeneity within ccRC across spatial samples in individual tumors, between patients, and under treatment with ICB has not been characterized. Leveraging a cohort of ICB naive and treated patients, we performed paired single cell RNA and T cell receptor sequencing of 167283 cells from multiple tumor regions, lymph node, adjacent normal kidney, and peripheral blood to map the immune landscape of ccRCC. We found striking immune heterogeneity within and between patients and in response to ICB, with enrichment of CD8 tissue-resident T cells in a patient with complete response and of tumor-associated macrophages in a patient with primary resistance. These immune populations were linked to tumor regression and grade respectively via pathologic review. Single cell T cell receptor profiling demonstrated that that CD8 tissue resident T cells expand after ICB administration, and moreover, that expanded intratumoral TCRs can be detected in normal kidney and peripheral blood. Finally, we associate immune populations identified via single cell analysis with widely used gene signatures associated with response to ICB, tyrosine kinase inhibitors, and combination regimens through re-analysis of bulk RNAseq profiles from over 1000 patients, suggesting a link between TAM phenotypes and angiogenesis-related signatures. Our analyses establish a comprehensive, high resolution, multimodal interrogation of intratumoral immune heterogeneity in the ccRCC microenvironment and suggest associations between immune populations and treatment outcome.