Soluble MAdCAM-1 as a biomarker in metastatic renal cell carcinoma
Carolina Alves Costa Silva, Marc Machaalani, Renée Maria Saliby, Caiwei Zhong, Wanling Xie, Edoardo Pasolli, Gianmarco Piccinno, Cécile Dalban, Marine Fidelle, Aurélia Meurisse, Dewi Vernerey, Gwo‐Shu Mary Lee, Roxanne Birebent, Eddy Saad, Clara Steiner, Ronan Flippot, Janice Barros-Monteiro, Nicola Segata, Antoine Thiery-Vuillemin, Silvia C. Formenti, Tatiana Kuznetsova, Bernard Escudier, Lisa Derosa, Laurence Zitvogel, Toni K. Choueiri, Laurence Albigès
Abstract
Patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors or antiangiogenic tyrosine kinase inhibitors may develop resistance driven by gut dysbiosis, which disrupts the MAdCAM-1–α4β7 axis and promotes the recruitment of immunosuppressive IL-17-producing T regulatory (Tr17) cells into tumors. We evaluated soluble MAdCAM-1 (sMAdCAM-1) as a prognostic biomarker in 1,051 patients from three cohorts: JAVELIN Renal 101 (avelumab plus axitinib versus sunitinib), SURF (sunitinib) and NIVOREN (nivolumab after tyrosine kinase inhibitors). In the JAVELIN cohort, baseline sMAdCAM-1 levels >180 ng ml−1 were associated with significantly improved progression-free survival (13.9 versus 8.4 months, P < 0.01) and overall survival (18 months: 84.2% versus 68.1%, P < 0.01), independent of IMDC risk groups. We validated the prognostic value of sMAdCAM-1 for overall survival in the SURF and NIVOREN cohorts. Notably, low sMAdCAM-1 levels were associated with an immunosuppressive gut microbiota profile dominated by Enterocloster species. Therefore, sMAdCAM-1 deserves further investigations as a biomarker-guided tool for microbiota-targeted interventions. A clinical cohort-based biomarker study in patients with metastatic renal cell carcinoma demonstrates that blood levels of soluble mucosal addressin cell adhesion molecule-1 are prognostic for survival in patients treated with tyrosine kinase inhibitors and immune checkpoint inhibitors and may serve as a surrogate marker for gut dysbiosis based on integrated data from three clinical trials.