The critical need for effective therapy of fumarate hydratase-deficient renal cell carcinoma (FHRCC) is currently unmet. Researchers wanted to examine, at the single-cell level, the genetic features and microenvironment of FHRCC and the cause of uneven response to immune checkpoint inhibitor (ICI)-based treatment. About 30 patients with advanced FHRCC underwent whole-exome sequencing and immunohistochemical staining analyses. In 4 patients, RNA was sequenced from individual cells after they were treated with ICI. Data on clinical features, treatment outcomes, and follow-up were evaluated.
The tumor mutation burden was low, with only 0.14 mutations per megabase in the middle. Immunohistochemical labeling revealed a tumor microenvironment rich in CD8+ T cells, indicating immunological activity. The fraction of CD8+ T lymphocytes that infiltrated the tumor were inversely linked with ATM expression. While CD8+ T cells were continuously exposed to ICI-based therapy, a trajectory analysis revealed gradually raised tired markers and an enhanced apoptotic trend. The overall response rate was higher with ICI-based treatment (17.6% vs. 0%, P = 0.046), and the disease control rate (DCR) was higher with ICI-based treatment (64.7% vs. 12.5%, P = 0.004) than with a tyrosine kinase inhibitor.
In patients with a germline mutation, ICI-based treatment resulted in a greater ORR (16.7% vs. 0%, P = 0.086) and DCR (66.7% vs. 14.3%, P = 0.011). It is common for the immune system to infiltrate FHRCC tumors. Response to treatment with ICI-based regimens is reliant on the physiologic state of tumor-infiltrating lymphocytes; therefore, understanding their function is crucial. In individuals with progressing illness, ICI-based treatment is unable to halt CD8+ T cell exhaustion, underlining the need for supplementary therapeutic approaches.
