Novel insights into chromophobe renal cell carcinoma biology and potential therapeutic strategies

New Haven, Conn. — Cancer fighting T-cells, the immune system’s primary enforcers, are scarce in the rare kidney cancer called chromophobe renal cell carcinoma (ChRCC) and those that are present are indifferent to the tumor threat and traditional immune therapies, revealing the need for new targets and treatments.

Those are among the results described in a July 2 published report in the Journal of Clinical Oncology that set out to understand the biology of certain kidney tumors, including ChRCC, and their immune responses.

The study found that ChRCC, which accounts for about 5 percent of all kidney cancers, has fewer T-cells and key molecules required for an immune response than other kidney cancers and poorer response and survival rates when treated with immune-based therapies. Other examined kidney tumors included in the study were Low-grade oncocytic tumor (LOT) and the usually benign renal oncocytoma (RO).

“Chromophobe renal cell carcinoma remains a major challenge to treat in the clinic, in large part because we do not have a deep understanding of the underlying biology. Most of the available treatments were developed for other types of kidney cancer, and do not take into account the unique immune features of this rarer cancer type,” said Yale Cancer Center’s David Braun, MD, PhD, corresponding author of the study.

This study was co-led by other senior others Elizabeth P. Henske, MD of Brigham and Women’s Hospital in Boston, Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, Eliezer M. Van Allen, MD, of Dana-Farber Cancer Institute, and Sachet Shukla, PhD, of MD Anderson Cancer Center. The first author of the study was Chris Labaki, MD, now at the Beth Israel Deaconess Medical Center. It also included several dozen researchers from institutions in the US and Canada.

The study’s detailed machine learning analysis of individual cells from ChRCC tumors, as well as normal tissue, helped determine the origin of the tumor from a specific type of kidney cell, α-intercalated cells. Researchers identified genes activated or deactivated in ChRCC tumors compared to the original normal cell. The study further used single-cell sequencing analysis of immune cells in the tumor to learn how ChRCC cancer cells actively hide from the immune system.

“For many more common types of kidney cancer, that 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,” said Braun, a researcher in YCC’s Center of Molecular and Cellular Oncology and assistant professor of medicine, pathology, and urology at Yale School of Medicine.

While providing new understanding of ChRCC and treatment pathways that could be explored, the study noted limitations, including sample size and the need for further research.

Funding for this work includes the U.S. Department of Defense (award W81XWH-19-1-0550), the US DOD Early Career Investigator Grant (KCRP AKCIECI, W81XWH-20-1-0882), the Kidney Cancer Association (KCA) Trailblazer Award, the Louis Goodman and Alfred Gilman Yale Scholar Fund, the National Institutes of Health, National Cancer Institute (1R37CA279822-01), and the Yale Cancer Center (supported by NIH/NCI research grant P30CA016359). This project was supported in part by a KCRP award the Tuttle Family, and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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