Dr Katims on Characterizing Immune Phenotype in FGFR3-mutated Upper Tract Urothelial Carcinoma

Andrew Katims, MD, MPH, urologic oncology fellow, Memorial Sloan Kettering Cancer Center, discusses research characterizing immune responses in the tumor microenvironment of FGFR3-mutated upper tract urothelial carcinoma using single-cell RNA-sequencing (scRNA-seq).

Patients with upper tract urothelial carcinoma commonly harbor FGFR3 mutations. As patients with this tumor type often experience poor responses to immune checkpoing blockade, FGFR mutations have been implicated in the impairment of T-cell responses in the tumor microenvironment.

As such, a study utilizing scRNA-seq was performed to better characterize the immune phenotype of these tumors. Seven individual tissue samples were obtained from patients who were treatment naïve. The phenotype of defined cell clusters and immune composition in the tumor tissue was analyzed using scRNA-seq.

A total of 19 immune cell clusters with unique biologic functions were identified, including 8 T-cell clusters, Katims reports. Clusters were categorized into FGFR3-mutated vs FGFR3-unmutated samples, he states. Overall, patients with FGFR-mutated disease had a T-cell phenotype characterized by a high frequency of active/exhausted Th17-like CD4 cells, lower levels of regulatory T cells, and increased amounts of CD8/cytotoxic cells in naïve state.

Findings from this study were consistent with previous data showing that FGFR3-mutated tumors are associated with high T-cell infiltration, Katims continues. This was particularly noted in cluster 3 of the CD8 compartment. CD8 cells were primarily in a naïve state and were associated with lower exhausted/active markers, lower rates of cytotoxic activity, leukocyte apoptotic process, and alpha-beta T-cell differentiation regulation, Katims states. Accordingly, the tumor microenvironment appears to be less robust in these patients. Moreover, the high level of plasma cell infiltration and Th17 in the CD4 compartment potentially signals the presence of tertiary lymphoid structures in these tumors, he adds.

Although findings from this study do indicate specific functional traits of various T-cell compartments in urothelial carcinoma, the large amount of data produced by scRNA-seq requires substantial analysis and should be used to ask many more clinically relevant questions, Katims explains. Ultimately, these data could ultimately inform efforts to activate T-cell response and maximize therapeutic benefit for these patients, Katims concludes.