Chromophobe Renal Cell Carcinoma - Beyond the Abstract
Translational and clinical progress in most vhRCC has lagged compared to ccRCC, in which there is proven clinical efficacy of immune checkpoint blockade and tyrosine kinase inhibitors. It is clear that progress in ChRCC requires a deeper understanding of pathogenic mechanisms, which appear almost entirely distinct from ccRCC and other vhRCC.
ChRCC is believed to originate from the specialized mitochondria-rich intercalated cells of the distal nephron, which are responsible for acid-base regulation by secreting H+ ions via the vacuolar ATPase (v-ATPase). ChRCC is characterized by mitochondrial dysfunction (sometimes accompanied by mitochondrial DNA mutations) and exceptionally high levels of glutathione (GSH), up to 100 times higher in the tumor cells than matched normal kidney tissue. It is hypothesized that mitochondrial dysfunction leads to oxidative stress, with compensatory high levels of GSH. Importantly, inhibiting GSH synthesis, such as by blocking the uptake of cystine/cysteine, leads to ferroptotic cell death in models of ChRCC. Ferroptosis is an iron-dependent form of cell death triggered by oxidation of membrane phospholipids. Targeting ferroptosis may represent a novel therapeutic approach in ChRCC.
Interestingly, ChRCC can occur in two hereditary genetic diseases - Tuberous Sclerosis Complex (TSC) and Birt-Hogg-Dube syndrome (BHD) - that are associated with activation of the mechanistic target of rapamycin complex 1 (mTORC1), a distinct oncogenic event. Mutations in the PTEN gene and in genes such as TSC1/2 in the mTOR pathway occur in a subset of sporadic ChRCC, and mTORC1 inhibitory therapy has shown modest benefit in some ChRCC.
Understanding the tumor microenvironment of ChRCC could be key to developing new therapies. In contrast to other RCCs, ChRCC is considered immunologically ‘‘cold’’ with a poorly immune-infiltrated microenvironment and a lack of tumor-specific T cells. The limited response rate of ChRCC to available immune checkpoint inhibitors (ICIs) underscores our limited understanding of the distinct immunobiology of ChRCC. Recent work identified a targetable pathway with the potential for clinical translation: ChRCC was recently found to have abundant innate lymphoid cells type 1 (ILC1s) driven by IL-15, and both IL-15 and ILC1 gene signatures were correlated with improved overall survival. These findings provide a foundation for potential clinical trials investigating IL-15 therapy and emphasize the pressing need to understand the fundamental immunobiology of ChRCC.
In summary, ChRCC research stands at a turning point, with the prospect of pioneering targeted therapies based on the immune microenvironment and ferroptosis. Collaboration between multi-disciplinary teams will be critical to progress. Many questions remain, including elucidating the sarcomatoid variants of ChRCC, which exhibit higher clinical aggressiveness and metastatic potential. Overcoming challenges, including the need for improved cellular and mouse models and dedicated clinical trials, remains a high priority.
Written by: Elizabeth P. Henske & Melissa Daou, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
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