Memory/Active T-Cell Activation Is Associated with Immunotherapeutic Response in Fumarate Hydratase–Deficient Renal Cell Carcinoma

Abstract

Abstract Purpose: Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare and lethal subtype of kidney cancer. However, the optimal treatments and molecular correlates of benefits for FH-deficient RCC are currently lacking. Experimental Design: A total of 91 patients with FH-deficient RCC from 15 medical centers between 2009 and 2022 were enrolled in this study. Genomic and bulk RNA-sequencing (RNA-seq) were performed on 88 and 45 untreated FH-deficient RCCs, respectively. Single-cell RNA-seq was performed to identify biomarkers for treatment response. Main outcomes included disease-free survival (DFS) for localized patients, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for patients with metastasis. Results: In the localized setting, we found that a cell-cycle progression signature enabled to predict disease progression. In the metastatic setting, first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI+TKI) combination therapy showed satisfactory safety and was associated with a higher ORR (43.2% vs. 5.6%), apparently superior PFS (median PFS, 17.3 vs. 9.6 months, P = 0.016) and OS (median OS, not reached vs. 25.7 months, P = 0.005) over TKI monotherapy. Bulk and single-cell RNA-seq data revealed an enrichment of memory and effect T cells in responders to ICI plus TKI combination therapy. Furthermore, we identified a signature of memory and effect T cells that was associated with the effectiveness of ICI plus TKI combination therapy. Conclusions: ICI plus TKI combination therapy may represent a promising treatment option for metastatic FH-deficient RCC. A memory/active T-cell–derived signature is associated with the efficacy of ICI+TKI but necessitates further validation.