Chromophobe renal cell carcinoma (RCC) exhibits a fundamentally different immune landscape compared to clear cell RCC, characterized by an immune-cold environment that severely limits patient response to standard immunotherapy regimens, according to comprehensive research published in the Journal of Clinical Oncology.
The study, led by investigators from Yale Cancer Center, Dana-Farber Cancer Institute, and other major institutions, provides the first in-depth analysis of the tumor microenvironment and immune characteristics of chromophobe RCC, which accounts for approximately 5% of all kidney cancers but represents the second most common type of non-clear cell RCC.
Distinct Immune Profile Revealed
Using single-cell transcriptomic and T-cell receptor profiling on fresh tumor specimens from five patients with chromophobe RCC, researchers discovered marked differences in immune infiltration compared to clear cell RCC. The tumor microenvironment of chromophobe RCC showed significantly decreased immune infiltration (Wilcoxon P = .007), with a particularly striking depletion of tumor-infiltrating CD8-positive T cells at 9.6% versus 44.6% in clear cell RCC (Fisher's exact P < .001).
The proportion of CD4-positive T cells was similarly reduced in chromophobe RCC at 3.2% compared to 12.3% in clear cell RCC (Fisher's exact P < .001). Conversely, chromophobe RCC displayed higher proportions of B-lineage cells (20.6% vs 1.4%; Fisher's exact P < .001) and myeloid cells (34.7% vs 17.7%; Fisher's exact P < .001) compared to clear cell RCC.
Immunohistochemistry evaluation revealed that the few CD8-positive T cells present in chromophobe RCC had lower immune checkpoint expression, decreased tumor specificity, and reduced clonal expansion compared to clear cell RCC cells. The density ratio of PD-1 expression to CD8 expression trended lower in chromophobe RCC versus clear cell RCC (Wilcoxon P = .11), indicating a distinct immune phenotype with lower expression of clinically actionable immune checkpoints.
Cellular Origin and Therapeutic Targets Identified
Machine learning analysis of single-cell RNA sequencing data identified α-intercalated cells (ICA) as the cellular origin of chromophobe RCC and related renal oncocytic neoplasms. Differential gene expression analysis between chromophobe RCC and ICA cells revealed upregulation of genes including KLK1, NUPR1, FTL, and FTH1, with NUPR1, FTL, and FTH1 known to inhibit ferroptosis—a key molecular pathway that may represent a therapeutic vulnerability.
The most downregulated genes included HLA class I molecules (HLA-A, HLA-B, HLA-C), which are associated with immunotherapy resistance, and heat shock proteins (HSPA5, HSPA6, HSPA8, HSPA1A, HSPA1B) that suppress ferroptosis. This HLA class I downregulation coupled with ferroptosis pathway enrichment suggests potential therapeutic targets beyond traditional immunotherapy approaches.
Clinical Outcomes Confirm Poor Immunotherapy Response
Real-world clinical analysis using data from the International metastatic RCC Database Consortium examined outcomes in 229 patients with chromophobe RCC, including 31 who received standard-of-care immune checkpoint inhibitor-based therapy. These patients were compared against 8,931 patients with clear cell RCC, of whom 856 received ICI-based therapies in the first-line setting.
At a median follow-up of 58.6 months, patients with metastatic chromophobe RCC who received ICI-based treatment achieved a median overall survival of 24.7 months (95% CI, 16.0-not reached) versus 50.5 months (95% CI, 42.5-67.4) in those with metastatic clear cell RCC (adjusted HR, 2.80; 95% CI, 1.51-5.18). The median time to treatment failure was also inferior at 4.5 months (95% CI, 2.4-16.0) versus 11.0 months (95% CI, 9.8-13.6) in the clear cell population (adjusted HR, 2.23; 95% CI, 1.43-3.48).
Overall response rates demonstrated the stark difference in immunotherapy efficacy, with chromophobe RCC patients achieving only 12.0% response rates compared to 47.1% in clear cell RCC patients (adjusted odds ratio, 95% CI, 2.95-64.84). Notably, no patients with metastatic chromophobe RCC achieved complete responses to first-line ICI therapy, compared to 4.9% of clear cell RCC patients.
mTOR Inhibitors Show Promise
In contrast to the poor outcomes with immunotherapy, patients with metastatic chromophobe RCC treated with first-line mTOR inhibitors everolimus or temsirolimus achieved superior outcomes compared to clear cell RCC patients. The median overall survival was 41.3 months (95% CI, 14.4-not reached) versus 13.4 months (95% CI, 10.9-15.3) in clear cell RCC patients (adjusted HR, 0.77; 95% CI, 0.48-1.25). Similarly, median time to treatment failure favored the chromophobe population at 7.84 months (95% CI, 5.29-16.6) versus 3.45 months (95% CI, 2.99-3.98) in clear cell patients (adjusted HR, 0.52; 95% CI, 0.33-0.82).
Implications for Future Treatment Strategies
"Our study confirms the cellular origin of chromophobe RCC and identified several differentially expressed pathways, supporting the investigation of new targets for chromophobe RCC therapy, including ferroptosis, mTORC1 signaling, and IL-15 signaling," stated lead study author Chris Labaki, MD, an internal medicine resident at Beth Israel Deaconess Medical Center and research associate at Dana-Farber Cancer Institute.
David Braun, MD, PhD, corresponding author from Yale Cancer Center, emphasized the clinical implications: "For many more common types of kidney cancer, there are many immune cells that are present and capable of recognizing the tumor cells, but lack their normal function because they are 'exhausted.' Conventional immune checkpoint inhibition makes sense for those kidney cancers. For ChRCC, however, the mechanism of immune evasion is completely different. We therefore need therapeutic strategies that steer cancer-specific immune cells into the tumor."
The findings provide a mechanistic basis for the poor responses to immune checkpoint inhibitor therapies observed in chromophobe RCC and suggest that future immunotherapy strategies should focus on increasing tumor cell antigen presentation and expanding the repertoire of tumor-specific CD8-positive T cells that infiltrate the tumor microenvironment.
