Integrin β4 drives immune evasion and therapeutic resistance to PD-1 blockade in bladder cancer via MEK/ERK signaling

Bladder cancer (BLCA) is one of the most prevalent malignancies of the urinary system and accounts for 90 to 95% of urothelial carcinomas. Muscle-invasive BLCA (MIBC) is a malignant type of BLCA, with a 5-years survival rate of only 50%. While immune checkpoint inhibitors (ICIs) have shown promise in advanced MIBC, their responsiveness is limited by the immune evasion mechanisms in tumor cells. Integrin β4 (ITGB4), a member of the intercellular adhesion molecule family, is reported to be significantly upregulated in many cancers and implicated in tumor progression. Our previous work established that the elevation of ITGB4 in BLCA was closely related to cisplatin resistance. However, the role of ITGB4 in BLCA immunotherapy remains unclear. Through bioinformatics analysis, RNA sequencing, and cell-based assays, we demonstrate that ITGB4 modulates the anti-tumor immune response through tyrosine-1510 phosphorylation-dependent activation of the MEK1/ERK1/2/c-Jun signaling cascade, and the high expression of ITGB4 inhibits the anti-tumor efficiency of PD-1 blocking in BLCA. According to the latest sequential therapy recommendations in the BLCA diagnosis and treatment guidelines, antibody-drug conjugates (ADCs) have demonstrated relevant clinical benefits in patients with advanced BLCA who are refractory to platinum and ICIs. Our research also discovered a positive correlation between ITGB4 and the ADCs drug target NECTIN4, and the overexpression of ITGB4 upregulates BLCA sensitivity to enfortumab vedotin treatment. It provides a basis for the treatment choice of advanced BLCA patients with immunotherapy resistance. Collectively, these results suggest that ITGB4 may be a promising therapeutic target for advanced BLCA.