Immunotherapy has transformed cancer treatment for some patients, but a major problem persists: most people with melanoma don't benefit from these powerful drugs. Even though melanoma is considered one of the most responsive cancers to immunotherapy, with a 37% response rate, that means nearly two-thirds of patients see no benefit . Now, researchers at Fred Hutch Cancer Center are launching a groundbreaking investigation into why tumors outsmart our immune system and how to fix it.

Why Do Most Melanoma Patients Not Respond to Immunotherapy?

Immunotherapy works by reactivating the body's immune system to recognize and destroy cancer cells. In theory, it sounds straightforward. But in practice, tumors have evolved sophisticated ways to hide from our defenses. "While melanoma or MSI-high colorectal patients have the best chance of responding to these treatments, a large proportion of patients even in these responsive indications don't benefit," explained Kevin Barry, PhD, a molecular biologist at Fred Hutch Cancer Center . "Our immune system protects against cancer, and the new immunotherapies work by re-activating the immune system to kill cancer and, in some cases, essentially cure patients. But the immune system can be overrun by cancer. Only around 30% of patients respond to this type of treatment" .

Cancer cells employ several evasion tactics to avoid detection. These include immune cell exclusion, reduced recruitment of immune cells to the tumor, the production of immunosuppressive molecules called cytokines, and tumor cells downregulating neoantigen expression, which is how the immune system recognizes cancer as foreign . Understanding these mechanisms is critical to developing better treatments.

What Role Do Dendritic Cells Play in Tumor Immune Evasion?

Barry's research, funded by a $270,000, two-year grant from the American Cancer Society, focuses on a specific type of immune cell called conventional dendritic cells, or cDCs . These cells act as sentinels in tissues like skin, lungs, and the gut lining. They capture antigens from viruses, bacteria, or cancer cells and present them to T cells, essentially teaching the immune system what to attack. Think of dendritic cells as messengers between the innate immune system (the one we're born with) and the adaptive immune system (the one that learns and remembers specific threats).

There are two types of cDCs: cDC1s and cDC2s. Scientists have extensively studied cDC1s because they efficiently activate CD8 T cells, which are crucial for killing cancer. But cDC2s remain poorly understood, especially their role in shaping anti-tumor immune responses . Barry's team will investigate how cDC2 dysfunction in tumors allows cancer to evade the immune system and how these cells influence the protective CD8 T-cell responses that should be fighting melanoma.

How Will Researchers Boost Immunotherapy Response?

• Develop preclinical models: Barry's team will create laboratory models to test how cDC2 cells prime T-cell function in living organisms, moving beyond simple cell culture experiments.
• Map immune cell organization: Researchers will determine how the physical arrangement and characteristics of dendritic cells shape CD8 T-cell responses in actual human metastatic melanoma tissue samples.
• Identify novel therapeutic targets: By understanding how cDC2s suppress protective immune responses, the team aims to develop new immunotherapies that work alongside existing treatments to disrupt this immune tolerance and enhance patient survival.

"These studies will provide a novel understanding of the regulation of CD8 T-cell responses in cancer and will allow us to begin to develop treatments to disrupt the tolerogenic, or immune tolerant, role of cDC2s in cancer," stated Kevin Barry . "A significant output of our studies will be the future development of novel immunotherapies that work in concert with existing treatments to enhance survival of patients with primary and metastatic cancers" .

Barry chose to focus on melanoma because it has the longest history with immunotherapy and represents an ideal model for understanding how immune evasion works across solid tumors. "But we believe that what we learn from studying dendritic cells in melanoma will translate to other solid tumors, as well," he noted . Early research suggests that the pathways discovered in melanoma may apply to other cancer types, though scientists acknowledge uncertainty about whether findings will hold true for all solid tumors.

This research addresses a critical gap in cancer treatment. While immunotherapy has revolutionized outcomes for a small group of patients, the majority of people with melanoma and other cancers still lack effective options. By uncovering how tumors manipulate dendritic cells to suppress immune responses, Barry's team hopes to unlock new combination therapies that could transform immunotherapy from a treatment that works for some into one that works for many.