Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, diagnosed in about 76,000 people in the United States each year.
If caught early, treatments such as immune checkpoint blockade (ICB) therapy, which bolsters the body’s anti-tumor immune response, can slow cancerous growth. About 70% of people with small ccRCC tumors are alive five years after diagnosis.
Yet patients vary in their response to ICB therapy, and the mechanisms that determine responsiveness are not well understood.
Now, in a study led by Melissa Wolf, PhD, researchers at Vanderbilt University Medical Center have identified cancer cell-specific genetic alterations that reprogram the immune “landscape,” thereby driving tumor growth, and discovered a potential new drug target for stopping it.
Their paper, published April 15 in The Journal of Clinical Investigation, focuses on the von Hippel Lindau (VHL) gene, which normally regulates cell growth and division. Absence of or mutations in this gene are associated with the development of cancer, including ccRCC.
“We have known for many years that ccRCC cancer cells lose the von Hippel Lindau gene, and that this can change cell metabolism, but how that affects immune cells has been unknown,” said the paper’s corresponding author, Jeffrey Rathmell, PhD, director of the Vanderbilt Center for Immunobiology.
“Melissa identified those changes and a potential new target in ccRCC,” said Rathmell, the Cornelius Vanderbilt Professor of Immunobiology in the Department of Pathology, Microbiology and Immunology at VUMC.
The target is CX3CL1, a cytokine or signaling protein upregulated in cells that do not express the VHL gene. When VHL is absent, cancer-fighting white blood cells called T-cells become dysfunctional, and the response of ccRCC to PD-1 inhibition, a current, first-line ICB treatment for the disease, declines.
The VUMC researchers used a mouse model of kidney cancer to explore how loss of VHL impacts cellular metabolism and the tumor’s microenvironment, which includes both immune cells and inflammatory myeloid cells. While immune cells attack tumors, bone marrow-derived myeloid cells can enhance tumor growth.
The study found that VHL-deficient tumor cells have an increased production of CX3CL1, a signaling protein important in the recruitment of inflammatory myeloid cells into the tumor. When the CX3CL1 gene is deleted, myeloid infiltration slows and so does tumor growth.
The researchers cautioned that the effect of an absent or non-functional VHL gene may be more complex in humans. For example, another secretory factor, CXCL16, is also upregulated in VHL-knock out tumors, and may contribute to T-cell dysfunction, the researchers reported.
While further investigation is needed, “this work reveals a previously unknown way in which cancer cells impact the function of immune cells in the immediate region of the tumor in renal cell carcinoma,” Wolf said.
The upregulation of CX3CL1, a specific driver of myeloid inflammation, thus is a potential drug target for treating aggressive forms of the disease, she added.
Wolf, who began the work as a graduate student, conceived and designed the study with Rathmell and his wife and colleague Kimryn Rathmell, MD, PhD, MMHC, former chair of Medicine at VUMC who was appointed director of the National Cancer Institute in November. Wolf also analyzed the data.
VUMC co-authors are: Matthew Madden, MD, PhD, Emily Arner, PhD, Jackie Bader, PhD, Xiang Ye, PhD, Logan Vlach, Megan Tigue, Madelyn Landis, Zaid Hatem, KayLee Steiner, Dakim Gaines, MD, PhD, Bradly Reinfeld, Emma Hathaway, Fuxue Xin, Noor Tantaway, PhD, Scott Haake, MD, PhD, Alexander Muir, PhD, Vivian Weiss, MD, PhD, and Kathryn Beckermann, MD, PhD.
The research was supported in part by National Institutes of Health grants F31CA261049, F30CA239367, K00CA253718, K00CA234920, F30CA247202, R01CA217987, T32GM007347, and K12CA090625, the U.S. Department of Defense, and the Vanderbilt-Incyte Alliance.