Researchers at The University of Chicago recently published in the journal Nature the discovery of a melanoma-cell-intrinsic oncogenic pathway that can mediate cancer immune evasion by inhibiting T cells (the primary anti-cancer weapon of the immune system), leading to the development of resistance to cancer immunotherapies. The study is entitled “Melanoma-intrinsic β-catenin signaling prevents anti-tumor immunity.”
Melanoma is the most dangerous form of skin cancer that is caused by damage to skin cells (usually by ultraviolet radiation from sunshine or tanning beds), which triggers mutations that are not repaired, allowing cells to rapidly multiply and generate malignant tumors. Melanoma is curable when detected and treated early; if it goes undetected or if it recurs, the cancer can proliferate and spread (metastasize) to other parts of the body, becoming more difficult to treat.
The development of effective immunotherapeutic approaches, like the blockade of immune-inhibitory receptors on activated T cells through antibodies, has revolutionized melanoma treatment. However, only part of the patients is responsive to these therapies. It has been suggested that patients with a pre-existing T cell response against the tumor (like immune T cell infiltration within the tumor microenvironment) have better therapeutic benefits from immunotherapies.
“Understanding the molecular mechanisms behind the presence or absence of a spontaneous anti-tumor T cell response should help us predict which patients will respond to the new immunotherapies,” explained the study’s senior author Dr. Thomas Gajewski in a news release.
In the study, researchers conducted a molecular analysis of human metastatic melanoma samples from patients with T cell infiltration (106 individuals) or without it (91 individuals). The team found that the major difference between the two groups was the activation of a signaling pathway called WNT/beta-catenin, and that this correlated with the absence of a T-cell response. The WNT/beta-catenin is a tightly regulated pathway involved in several cellular processes including proliferation and differentiation. Mutations in the beta-catenin gene have been linked to a more aggressive tumor form in melanoma, lung, colon and prostate cancer. In this study, researchers found that 49% of the melanoma tumors that inhibited T cell infiltration had high levels of beta-catenin signaling, as well as of six genes targeted by beta-catenin.
“This is the first identified cell-intrinsic cancer-causing pathway that disrupts T cell infiltration in melanoma,” said Dr. Gajewski. “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.”
Using melanoma mouse models, the team discovered that tumor-intrinsic activated beta-catenin prevents T cell infiltration in the tumor microenvironment, and that the protected tumor sites lacked one important element of the immune system — dendritic cells. “We noticed that tumors with elevated beta-catenin lacked a subset of dendritic cells known as CD103+,” said the study’s lead author Dr. Stefani Spranger. Dendritic cells are scavengers that recognize invaders like pathogens and cancer cells, and present them to T cells to mount an immune response.
Researchers treated mice with two potent cancer immunotherapies currently available, the monoclonal antibodies anti-CTLA4 and anti-PD-L1. They found that melanoma tumors that lacked beta-catenin responded to the therapy, whereas tumors with beta-catenin failed to respond. “This ability to resist immunotherapy could only be overcome by injection of CD103+ dendritic cells directly into the tumor,” noted Dr. Spranger. “With that intervention, T cells were able to invade and accumulate in the tumor.”
The team concluded that melanomas that express tumor-intrinsic beta-catenin-signaling have a defective recruitment of CD103+ dendritic cells, which leads to an inhibition of T cell infiltration and resistance to immunotherapies. The results also suggest that researchers “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 (…) There is also growing interest in developing drugs that could block beta-catenin.” added Dr. Gajewski. “Although our study focused on melanoma, the WNT/beta-catenin signaling pathway seems to play a role in many tumor types.”
“We hope this work will help increase the percentage of patients who respond to immunotherapy,” concluded Dr. Spranger.
