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

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.

Figure 1.

Characteristics and somatic alterations in FH-deficient RCC. A, Oncoplot showing clinicopathologic features, germline and somatic FH alterations, and co-occurring somatic mutations (prevalence > 5%) in patients with FH-deficient RCC (n = 88); B, Lollipop plot showing positions of FH somatic and germline alterations.

Figure 2.

Identification of predictors for early progression in patients with localized FH-deficient RCC. A, Univariate and multivariate Cox regression analyses of disease-free survival (DFS). B, Differentially expressed genes between patients with early and late disease progression. C, Enrichment of hallmark cell-cycle signaling pathways in early progression group revealed by gene set enrichment analysis. D, Kaplan–Meier analysis of DFS in patients with localized FH-deficient RCC stratified by quartiles of cell-cycle progression scores.

Figure 3.

Treatment outcomes of patients with metastatic FH-deficient RCC. A, Kaplan–Meier analysis of progression-free survival in patients treated with first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (ICI+TKI) versus TKI monotherapy. B, Kaplan–Meier analysis of overall survival (OS) in patients treated with first-line ICI+TKI versus TKI monotherapy. C, Kaplan–Meier analysis of OS in patients treated with non–first-line ICI+TKI versus patients who never received ICI+TKI during the treatment history.

Figure 4.

Single-cell RNA-sequencing (RNA-seq) profiling of FH-deficient RCC and newly defined signature. A, Single-cell RNA-seq (scRNA-seq) cell atlas generated from five samples obtained from four FH-deficient RCC cases. B, UMAP plot of all T cells collected from five sample. C, Bar plots showing tissue distribution of the T cells. D, Dot plot of marker gene expression for the seven T clusters. E, Tissue prevalence of four T-cell clusters estimated by Ro/e score. F, GSEA analysis showing enrichment of activated CD4, activated CD8, central memory CD4, and effector memory CD8 signatures in responders in the bulk RNA-seq cohort. G, Responders had higher expression of FH-deficient RCC immune signature than non-responders in the bulk RNA-seq cohort; a P value was determined by the two-sided Wilcoxon rank-sum test. H, Kaplan–Meier analysis of progression-free survival in patients treated with first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy (ICI+TKI) separated by high and low FH-deficient RCC immune signature score in the bulk RNA-seq cohort. I, More IL7R⁺CD8/CD4⁺ cells in responders of ICI+TKI revealed by multiple immunofluorescences staining. J, The percentage of IL7R⁺CD8⁺ T cells, out of CD8⁺ T cells, in samples from non-responders and responders (top) and the percentage of IL7R⁺CD4⁺ T cells, out of CD4⁺ T cells, in samples from non-responders and responders (down); the P value was determined by the two-sided Wilcoxon rank-sum test. *, P < 0.05.