TIGIT and PD-1 expression atlas predicts response to adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer.

ABSTRACT

BACKGROUND: TIGIT and PD-1 are checkpoint receptors that could regulate the functional status of immune cells through independent pathways. However, the clinical significance of immune classification based on TIGIT and PD-1 expression remains unclear in muscle-invasive bladder cancer (MIBC). METHODS: Patients with MIBC from four independent cohorts were categorised into three clusters. Survival analysis conducted through Kaplan-Meier curves and Cox regression model. Immune contexture was measured by immunohistochemistry and CIBERSORT algorithm. Twenty-five fresh tumour tissue samples were utilised to evaluate functional state of CD8+ T cells by flow cytometry. RESULTS: Cluster I (TIGITlowPD-1low) contained widely poor immune infiltrates with higher FGFR3 mutation, Cluster II (TIGITlowPD-1high) exhibited a highly infiltrated contexture with increased cytolytic CD8+ T cells and had the best prognosis, Cluster III (TIGIThigh) presented a suppressive tumour microenvironment (TME) featured by exhausted CD8+ T cells and basal molecular subtype. Patients of Cluster III had the worst survival but could benefit more from adjuvant chemotherapy and anti-PD-L1 immunotherapy, and also presented limited FGFR3 signalling signature but activated immunotherapeutic and EGFR-associated pathway. CONCLUSIONS: TIGIT/PD-1-based risk stratification with distinct immune and molecular features could be served as a predictor for systematic therapeutic response including adjuvant chemotherapy and immunotherapy in MIBC patients.