Regulation of Immunotherapy Resistance in CDKN2A-low Melanoma
Raquel Buj, PhD
|Katherine Aird, PhD; John Kirkwood, MD
|Career Development Award
|University of Pittsburgh
About 40% of melanoma patients have decreased p16, a tumor suppressor protein that inhibits cell proliferation. However, our laboratory and others have found that p16 can regulate other processes besides cell proliferation. Among them, recent indirect evidence suggests that loss of p16 is linked with resistance to immune checkpoint blockade (ICB) therapies, a current standard-of-care for melanoma patients. However, no study has directly demonstrated this relationship nor investigated a molecular reason. Understanding this link is critical to design efficient therapeutic regimens for the large subset of melanoma patients with decreased p16.
Our preliminary data using mouse models has shown for the first time, and in a direct manner, that melanoma tumors with decreased p16 are resistant to ICB therapies. Comprehensive analysis of these mouse tumors, as well as human melanoma tumors, showed that melanoma with decreased p16 increases the secretion of a protein called IGFBP-2. In some cancer models, IGFBP-2 has been shown to modify macrophages. Macrophages are a cell type that reside inside the tumor to help the body’s immune system fight tumor progression. Interestingly, we found that both human and mouse tumors with decreased p16 accumulate a specific type of macrophage, called alternatively-activated macrophages, that decreases the ability of the immune system to fight and can promote ICB resistance. Therefore, we think that increased IGFBP-2 in melanomas with decreased p16 promotes the observed ICB resistance. In this proposal, we aim to investigate whether limiting IGFBP-2 in melanomas with decreased p16 will avoid alternatively-activated macrophages accumulation and hence resensitize these tumors to ICB therapies.
Successful completion of these studies will improve the treatment for melanoma patients with decreased p16 (~40%) who are likely resistant to current standard-of-care ICB therapies.