Vanderbilt investigators have revealed the mechanisms by which the chemokine receptor CXCR2, is associated with melanoma tumor formation and growth — a discovery that supports the continued development of drugs that inhibit the receptor’s activity.
Ann Richmond, PhD, Ingram Professor of Cancer Biology and professor of Pharmacology, is internationally known for her research on chemokines and was the first to demonstrate that a chemokine can regulate tumor growth.
“Chemokines produced by tumor cells are known to attract certain suppressive immune cell populations into the tumor microenvironment, where they can help prevent an antitumor immune response and allow the tumor to grow unchecked,” said Richmond, the study’s senior author.
“Some chemokines can also bind receptors directly on the cancer cells themselves, increasing signaling that makes the tumor more aggressive. CXCR2 is one such receptor known to impact both immune and cancer cells.”
Previous investigations by the lab demonstrated the potential benefit of combining an inhibiting drug for the chemokine receptor CXCR2 with an immunotherapy for the treatment of metastatic melanoma. Although the Vanderbilt study was conducted in mouse models and cell lines so that melanoma could be induced and studied in a controlled environment, an ongoing clinical trial is evaluating the efficacy of such a drug combination in patients with metastatic melanoma. The phase 1 trial involves the combination of an experimental drug (SX-682) that is a CXCR1/CXCR2 inhibitor with the immunotherapy, pembrolizumab.
While this prior work in the Richmond lab showed that CXCR2 expression on a subset of immune cells is critical for recruitment of immunosuppressive myeloid cells that protect the tumor, this latest work sought to examine the receptor’s role within the developing tumor cells themselves.
In this recent study published in Molecular Cancer, her lab established the direct role that CXCR2 plays in tumor precursor cells as they acquire mutations and develop into full-fledged tumors. The work was led by staff scientist Jinming Yang, PhD, postdoctoral fellow Kensey Bergdorf, PhD, and research assistant professor Chi Yan, PhD.
Yang, one of the study’s first authors, developed a new mouse model to specifically find answers to the inquiry. The research team induced oncogenic mutations in only the melanoma precursor cells (melanocytes), and at the same time they were able delete CXCR2 in those same cells such that the CXCR2 gene was lost when the oncogenic mutations were introduced. They then delineated the changes that occur in tumors with or without loss of CXCR2 expression in developing tumor cells by evaluating gene expression, protein production and modification, transcription factor activity, and immune cell recruitment.
The researchers found that in three different models where CXCR2 signaling was decreased, one gene stood out as being significantly upregulated: TFCP2L1, which may act as a tumor suppressor in melanoma.
Other Vanderbilt authors who contributed to the study are Sheau-Chiann Chen, PhD; Gregory “Dan” Ayers, MS; Qi Liu, PhD; Xiao Liu, PhD; Mark Boothby, MD, PhD; Vivian Weiss, MD, PhD; Sarah Groves, PhD; Austin Oleskie; and Vito Quaranta, MD.
The research received funding with grants from the National Institutes of Health, the Department of Veterans Affairs, and the Henry J. Lloyd Charitable Trust.