Uveal melanoma, sometimes called ocular melanoma, is a type of cancer that affects the uvea, the middle layer of the eye that contains blood vessels, pigment cells (melanocytes), and provides nutrients and oxygen to the retina. Most uveal melanomas are still only within the eye when they are first diagnosed. It is rare for the cancer to have already spread outside of the eye. But unfortunately, in about half of all patients, the melanoma will come back at some point after treatment. Now, new research from the University of Pittsburgh explains why metastatic uveal melanoma is resistant to conventional immunotherapies and suggests how adoptive therapy can successfully treat this rare and aggressive cancer.

Their findings are published in Nature Communications in an article titled, “Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.”

“The dogma was that uveal melanoma is a ‘cold’ cancer, meaning that T cells can’t get into these tumors,” said senior author Udai Kammula, MD, associate professor of surgery at Pitt and director of the solid tumor cell therapy program at UPMC Hillman Cancer Center. “We show that T cells are in fact infiltrating metastases and they’re getting activated, but they’re just sitting there in a dormant state because something in the tumor is suppressing them. Adoptive therapy allows us to rescue these cells from the suppressive tumor microenvironment and successfully treat some patients.”

When metastasis occurs, this cancer is very difficult to treat and the prognosis for patients is almost always grim.

“Cutaneous melanoma, which affects the skin, is the poster child of immunotherapy. It responds incredibly well to immune checkpoint inhibitor drugs,” said Kammula. “None of these conventional immunotherapies work for uveal melanoma, but we hadn’t known why—until now.”

In a previous study, Kammula and his team used adoptive therapy to surgically extract metastatic tumors from 19 uveal melanoma patients and grow T cells from these tumors in the laboratory. When they infused the cells back, 35% of patients had either partial or complete regression of their cancer, evidence against the assumption that cancer-fighting cells called tumor-infiltrating lymphocytes (TILs) aren’t found in uveal melanoma. However, it was still a mystery why immune checkpoint inhibitors are ineffective in treating this disease.

Kammula saw an opportunity to answer this question using a unique resource that he and his team have been building for the last decade: the largest known repository of uveal melanoma samples, corresponding tissues, and clinical information.

When the researchers analyzed 100 metastases from 84 patients, they found that over half of these tumors were chock-full of T cells. Next, they performed single-cell RNA sequencing to measure gene expression in almost 100,000 cells from six metastases. They found that the TILs in some of these tumors were activated and capable of attacking tumor cells in a dish, but they weren’t proliferating to high numbers in the tumor.

“We found that TILs from metastatic uveal melanoma have the potential to attack the tumor, but something in the tumor microenvironment is shutting them down, so they’re in a dormant, or quiescent, state,” explained Kammula. “By liberating these cells from the suppressive environment and growing them in the lab, we can rescue their tumor-fighting capacity when infused back into the patient.”

To predict which patients will respond and which will not, Kammula and lead author Shravan Leonard-Murali, MD, PhD, a post-doctoral fellow in the lab, developed a clinical tool called Uveal Melanoma Immunogenic Score (UMIS), a holistic measure of the tumor that reflects the activity of more than 2,000 genes expressed by tumor cells, immune cells, and other cells that form the tumor microenvironment. UMIS ranged from 0.114 to 0.347 across 100 metastases, with higher values indicating tumors with more potent TILs.

Kammula is now evaluating the score prospectively in an ongoing TIL therapy clinical trial at Pitt for patients with metastatic uveal melanoma.

He and his team are also taking what they’ve learned to combat other difficult-to-treat tumors such as pancreatic cancer, and they are developing a pan-cancer version of UMIS that will predict how well a patient with any type of cancer is likely to respond to adoptive therapy.

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