# Expression Profiles of Co-Inhibitory Receptors in Non-Urothelial Bladder Cancer: Preclinical Evidence for the Next Generation of Immune Checkpoint Inhibitors

## TL;DR

This study explores immune checkpoint proteins in non-urothelial bladder cancer, finding differences in their expression that could guide future immunotherapy treatments.

## Contribution

The study identifies distinct expression patterns of TIM-3, TIGIT, and LAG-3 in bladder cancer subtypes, offering new therapeutic targets.

## Key findings

- TIM-3 and TIGIT are highly expressed in both SCC and ADENO, while LAG-3 is absent in ADENO.
- TIM-3 infiltration correlates with worse progression-free survival in SCC.
- TIGIT expression varies by age and gender in different cancer subtypes.

## Abstract

This study examines the expression patterns of new immune co-receptors in variant histology bladder cancer. TIM-3, TIGIT, and LAG-3 show differential expression in squamous-cell and adenocarcinoma, varying by age and gender. Biomarker testing is essential for future trial success.

Immune checkpoint inhibition is a cornerstone of bladder cancer therapy, but its efficacy in non-urothelial subtypes of bladder cancer is limited, and the prognosis remains poor. Therefore, we investigated the potential of the immune checkpoint molecules TIM-3, TIGIT, and LAG-3 in squamous-cell carcinoma (SCC) and adenocarcinoma (ADENO) of the urinary bladder. Tumor-infiltrating lymphocytes (TILs) showed a high expression of TIM-3 and TIGIT in both SCC and ADENO, while LAG-3-positive TILs were absent in ADENO and present in 46% of SCC. Quantitative analysis revealed age-independent expression of TIM-3 in SCC (r = −0.001, p = 0.997) and ADENO (r = 0.135, p = 0.549), with increasing age correlating with higher expression of TIGIT (r = 0.157, p = 0.242) and LAG-3 (0.106, p = 0.436) in the SCC cohort and of TIGIT (r = 0.276, p = 0.214) in the ADENO cohort. Male patients showed increased TIGIT scores in ADENO (p < 0.01). Of note, a high infiltration of TIM-3-TILs (p = 0.048) correlated with worse progression-free survival in SCC. These results highlight the differential expression of co-inhibitory receptors in non-urothelial bladder cancer subtypes and provide preclinical evidence for new therapeutic targets. Biomarker testing prior to clinical trials is essential for identifying the most suitable patients for targeted immunotherapy.