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Abstract Background Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn’s disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. Methods We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect of resolving inflammation on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 65 case subjects receiving vedolizumab were matched with biopsies from 65 control individuals, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full messenger RNA transcriptome sequencing of sorted T cells. Results No difference was seen between vedolizumab recipients and control individuals in the quantity of any antigen-experienced T lymphocyte subset or in the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than control individuals, regardless of response. However, the most striking finding was a marked reduction in CD1c+ (BDCA1+) dendritic cells exclusively in vedolizumab-responsive patients. In blood, these dendritic cells ubiquitously express high levels of α4β7, which is rapidly downregulated upon vedolizumab exposure. Conclusions The clinical effects of vedolizumab reveal integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to inflammatory bowel disease pathogenesis. Lay Summary Vedolizumab had no effect on the number or gene expression of memory T lymphocytes in the colons of recipients relative to control individuals. However, the colons of vedolizumab-responsive patients had distinctly fewer dendritic cells, which in blood express the most integrin α4β7.

BackgroundRenal cell carcinoma (RCC) responds to immunotherapy despite its low tumor mutational burden (TMB). Interestingly, the degree of CD8+ T cell infiltration in RCC negatively correlates with outcomes, suggesting that a deeper understanding of the tumor microenvironment may provide critical insight to improve outcomes.MethodsMulti-omics approaches including flow cytometry, scRNA-seq, scTCR-seq, and CITE-seq were used to compare immune cell composition, gene expression, and cell-cell interactions among a cohort of primary breast cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, and RCC specimens. Putative tumor specificity was determined by flow cytometry following coculture with autologous tumor cells.ResultsFlow cytometry analysis of tumor-infiltrating lymphocytes (TILs) revealed increased exhausted CD8+ (Tex) and CD4+CD8+ T cells and decreased CD4+ T cells including regulatory T cells in RCC compared to other tumors. scRNA-seq analysis confirmed these results and highlighted Tex cells as a major population of CD8+ T cells. Biomarker analysis of tumor-reactive CD8+ T cells (4-1BB+, CD39+CD103+) as well as a gene signature indicative of neoantigen reactivity, revealed that Tex and CD4+CD8+ T cell populations contain putative tumor-reactive T cells. Tumor reactivity of CD4+CD8+ T cells was demonstrated by increased 4-1BB and OX40 expression following restimulation with autologous tumor cells.ConclusionsExhausted CD8+ and CD4+CD8+ T cells in RCC contain tumor-reactive T cells and may represent a novel cell population capable of targeting RCC, suggesting additional functional characterization of these populations is warranted. Understanding mechanisms of T cell exhaustion and its reversal also has important implications for therapeutic treatment of RCC and other TMB-low, potentially immunotherapy-refractory, tumors.Ethics ApprovalSigned informed consent was obtained before enrollment. The study was approved by the Providence St. Joseph Health Institutional Review Board – Oregon (IRB #06-108).