Session: PD25: Bladder Cancer: Basic Research & Pathophysiology II
PD25-11: Clinical Significance of combinatorial blockade of novel immune checkpoint B7-H4 with PD-L1 in Urothelial Carcinoma of Bladder: A rational therapeutic approach
All India Institute of Medical Sciences, New Delhi , India
Introduction: Urothelial carcinoma of bladder (UBC) is complex disease with high mortality and recurrence rates. Current standard regimens have exhibited anti-tumor activity however, a proportion of patients are non-responsive or ineligible to receive such treatments, which stresses upon identifying new effective options for treating UBC. Immune checkpoints have emerged as potential class of therapeutics to be tested in UBC treatment. Methods: 40 UBC patients and 30 healthy controls were recruited from whom blood was taken. Histopathologically proven tumors and adjacent normal tissue were obtained from patients. Frequency of T cells and immune checkpoints (B7-H4 and PD-L1) was assessed in circulation. Molecular expression of immune checkpoints has been studied in tumor and normal tissue. In-vitro blocking of B7-H4 alone and in combination with PD-L1 was performed to test for T cell functionality. Finally, these immune checkpoints were correlated with clinico-pathological parameters Results: The relative mRNA expression of B7-H4 was found to be significantly elevated in tumor tissue compared to normal adjacent tissue (p=0.0007). PD-L1 exhibited a heightened expression in tumor tissue than its normal counterpart (p=0.004). When the expression was evaluated between non-muscle invasive and muscle-invasive bladder cancer patients, B7-H4 expression was observed to be significantly elevated in MIBC than in NMIBC patients (p < 0.0001). Similarly, PD-L1 showed a significant increase in muscle invasive bladder cancer patients (p= 0.001). Blockade of B7-H4 significantly increased the production of granzyme B and IFN-? in CD8+ cell and CD4+T cells. Importantly, co-blockade of B7-H4 and PD-L further significantly enhanced the capacity of CD8+ cells to produce IFN-? and granzyme B against cancer cells Conclusions: Overall, our data showcase that B7-H4 and PD-L1 expression was higher in T cells of UBC patients compared to healthy controls in peripheral blood. Upon stratifying patients with muscle invasive and non- muscle invasive bladder cancer their expression was increasing with disease severity and might be suggesting that cancer cells are constantly trying to escape the immune evasion by CD8 T cells. This maiden study highlights B7-H4 as a novel target showing a trend similar to PD-L1. Taken together, our results provide a rationale for the co-blockade of B7-H4 and PD-L1 in UBC patients for better treatment in future after validation. SOURCE OF Funding: All India Institute of Medical Sciences, New Delhi Intramural grant
