The Impact of Heterogeneity on the Effectiveness of Immune Checkpoint Inhibitors: A Case Series on Metastatic Urothelial Carcinoma

Abstract

Abstract Purpose: To investigate the disparities in tumor parenchyma and microenvironment between primary tumors and metastasis of urothelial carcinoma. Additionally, the study aims to determine whether the heterogeneity in these factors affects the predictive effectiveness of immune checkpoint inhibitors. Methods: In this retrospective study, we investigated the treatment outcomes of 5 patients with metastatic urothelial carcinoma who were treated with first-line immune checkpoint inhibitors. We analyzed various biomarkers including genomic profile, programmed cell death receptor ligand-1 expression, tumor mutation burden, microsatellite instability, T-cell ratio, and tertiary lymphoid structure in both primary and metastatic samples. Additionally, we collected and analyzed relevant clinical data. Results: At the genetic level, the main different genes were TSC1/2, MCL1, RAC1. TSC1/2 and MCL1 were acquired by metastases and RAC1 were lost by metastases. There were differences in programmed cell death receptor ligand-1, tumor mutation burden, T-cell ratio, tertiary lymphoid structure . All tumors in this study were microsatellite stable. In two patients with clinical disease control, the proportion of CD3+ T cell and CD8+ T cell in metastases increased compared with the primary tumors, and tertiary lymphatic structure changed from negative to positive expression. These results suggest that metastases may have more lymphocytic infiltrates and some form tertiary lymphoid structures, and patients with this feature may respond better to immune checkpoint inhibitors. Conclusions: The analysis revealed both similarities and differences between primary and distant metastasis samples in the context of urothelial carcinoma. We strongly advocate for re-biopsy of metastases following the occurrence of metastases and suggest that treatment methods should be chosen based on the detection of these metastases.