In a new study entitled “Melanoma-intrinsic β-catenin signaling prevents anti-tumor immunity,” a research team at University of Chicago unraveled the mechanism by which melanoma tumors are able to resist to the most effective immunotherapies currently available. These findings identify new candidate targets for developing immune tools to overcome tumor immune evasion pathways. The study was published in the May 11, 2015 issue of Nature.
Current front-line melanoma treatment includes effective immunotherapeutic approaches, particularly the use of monoclonal antibodies, to inhibit the expression of immune-inhibitory receptors at the surface of immune cells. However, it has been recognized that only a small fraction of melanoma patients benefit from these treatments — those whose tumors already present some infiltration of T cells within the tumor microenvironment.
A team of researchers at University of Chicago investigated which pathways underlie either the presence or absence of a spontaneous anti-tumor T-cell response. To this end, the team analyzed tumor tissue samples from melanoma patients — with 91 patients lacking T cell invasion while 106 patients exhibited inflammation driven by T cell infiltration. By comparing the genetic profile between these two subsets, authors identified active beta-catenin signaling as the major difference between both groups. Specifically, the team discovered that 94% of tumors lacking infiltration of T cells exhibited high levels of beta-catenin signaling, while only 4% of T cell infiltrated tumors expressed high beta-catenin activation.
To understand how activating beta-catenin signaling allowed tumors to prevent inflammation and block T cell infiltration, the team performed in vivo experiments with autochthonous mouse melanoma models (engineered by introducing directly into mice cancer-causing genetic alterations). With these experiments the team discovered the mechanisms by which tumor-activating beta-catenin signaling prevents T cell infiltration and allows the tumor to resist monoclonal antibody-based therapy, as Stefani Spranger, PhD, post-doctoral fellow in the University of Chicago’s Department of Pathology and study co-author explained, “We noticed that tumors with elevated beta-catenin lacked a subset of dendritic cells known as CD103+. Tumor cells without beta-catenin produce an immune-signaling molecule known as CCL4, which attracts CD103+ dendritic cells. But CCL4 expression is suppressed by tumor cells with high beta-catenin levels.”
The newly discovered mechanism allowed the team to understand why certain melanoma patients resist potent immunotherapies currently available. By treating mice with monoclonal antibodies, anti-CTLA4 and anti-PD-L1, they observed that only tumors lacking beta-catenin responded to treatment. Notably, “This ability to resist immunotherapy could only be overcome by injection of CD103+ dendritic cells directly into the tumor. With that intervention, T cells were able to invade and accumulate in the tumor,” Spranger commented.
Therefore, the team highlighted, “the major immunologic defect in the context of melanomas expressing tumor-intrinsic beta-catenin-signaling is defective recruitment of CD103+ dendritic cells.”
Thomas Gajewski, MD, PhD, professor of medicine and pathology at the University of Chicago and study lead author commented, “This is the first identified cell-intrinsic cancer-causing pathway that disrupts T cell infiltration in melanoma. This pathway enables multiple tumor types to evade immune surveillance. Developing strategies to inhibit this signaling within tumor cells could help restore T cell access and enhance the potential of immune-mediated cancer treatment. It also suggests we could develop ways to help patients who don’t initially respond to immune-mediated treatment, such as direct injection of their own CD103+ dendritic cells. Or we could use a short course of focused radiation therapy, which causes inflammation of tumor tissue and increased immune vigilance. There is also growing interest in developing drugs that could block beta-catenin. Although our study focused on melanoma,” he added, “the Wnt/beta-catenin signaling pathway seems to play a role in many tumor types.”