8The actionable microbial gut checkpoint MAdCAM-1 in patients with advanced renal cell carcinoma

Abstract Background Despite therapeutic advances, treatment resistance remains a major clinical challenge in advanced RCC (aRCC). The MAdCAM-1/α4β7 axis plays a pivotal role in mediating immune-microbial crosstalk, contributing to gut dysbiosis-associated treatment resistance. In this study, we evaluated the clinical relevance of both baseline levels and longitudinal dynamics of soluble MAdCAM-1 (sMAdCAM-1) as a biomarker of dysbiosis-related immune dysregulation in aRCC patients. Methods We measured sMAdCAM-1 in plasma samples from 612 patients treated in the phase 3 JAVELIN Renal 101 (1st line avelumab + axitinib vs. sunitinib, NCT02684006), 278 patients treated in the phase 2 NIVOREN (>2nd line nivolumab post-TKI, NCT03013335) and the prospective study ONCOBIOTICS (with paired with fecal metagenomics, NCT04567446) using a Luminex assay. Quantitative data are described by the number of patients with available data, the number of missing values, the mean, standard deviation, median, minimum and maximum values, and the 1st and 3rd quartile values (Q1-Q3). Optimal cutoff was determined using the maximum log-rank statistic. Cox regression models analyzed associations with progression-free survival (PFS) and overall survival (OS). We profiled each metagenome’s taxonomic composition with MetaPhlAn-4. For alpha diversity, we computed the per-sample Richness and Shannon indexes using the vegan R package. Differences between groups were assessed using the Wilcoxon-Mann-Whitney test. For beta-diversity, we computed the between-samples Bray-Curtis dissimilarities using the implementation available in the Vegan R package. Differential abundance analysis on taxonomic profiles between groups were performed using the LefSE software. Results The OS-based optimal cutoff was 180 ng/ml (25% percentile) in the JAVELIN Renal 101 population. Patients with higher sMAdCAM-1 at baseline demonstrated significantly improved survival outcomes: progression-free survival of 13.9 vs. 8.4 months (P < .01) and 18-month overall survival (OS) of 84.2% vs 68.1% (P < .01). These associations remained independent of IMDC risk group. Combining sMAdCAM-1 with IMDC scores improved 18-month OS prediction (AUC: 0.72 vs. 0.68, P = .01). We further evaluated sMAdCAM-1 dynamics between cycles 1 and 3 in the JAVELIN Renal 101 trial. Persistently low sMAdCAM-1 levels were associated with poor survival across both treatment arms (Table 1). Patients harboring low sMAdCAM-1 level had a gut microbiota composition dominated by proinflammatory species such as Proteobacteria (Hafnia alvei, Suterella wadsworthensis), Paraprevotella clara, and Bacteroidales (Odoribacteraeae (Butyricimonas virosa), Rikenellaceae (Alistipes shahii, A. onderdonkii), Tanarellaceae (Parabacteroides merdae) family members. Additionally, low baseline sMAdCAM-1 correlated with elevated proinflammatory cytokines interleukin-6 (IL-6), IL-8, and VEGF levels in the JAVELIN Renal 101 and NIVOREN cohorts. Conclusions Baseline and persistently low sMAdCAM-1 levels demonstrated significant associations with inferior survival outcomes and a distinct pro-inflammatory microbial-immune phenotype in aRCC patients. Our findings position sMAdCAM-1 as both: (1) a dynamic biomarker for tracking dysbiosis-driven immune dysregulation, and (2) a potential therapeutic target for microbiota-directed interventions in treatment-resistant disease.