Finding that T cells can persist for years throughout skin and blood and understanding what defines such durable immune responses in melanoma patients will lead to better design of therapies to achieve such responses.Mary Jo Turk, PhD
Some melanoma patients respond very well to immunotherapy, experiencing a strong and long-lasting tumor regression. Some of these patients will also develop autoimmunity against their normal melanocytes—the cells that give rise to melanoma. This phenomenon is called vitiligo. Melanoma survivors with vitiligo have long been recognized as a special group with an outstanding prognosis, and a strong response of immune system cells called T cells.
Immunotherapy researchers at NCCC led by Mary Jo Turk, PhD, and surgical oncologist Christina Angeles, MD (now of University of Michigan), have discovered how a subset of T cells known as memory T cells are generated in melanoma survivors with vitiligo and able to function for years after a tumor is gone.
“We are trying to understand how immune responses against cancer can persist over long periods of time in patients who have excellent responses to immunotherapy,” says Turk. “Our study was aimed at discovering where T cells go, what they do and how long they last in these patients. Some T cells last a short time, but others, known as memory T cells, can last for years. The goal of this work was to understand how memory T cells are generated in these patients.”
Turk and Angeles found that T cells that enter melanoma tumors also tend to enter a patient’s vitiligo-affected skin and that vitiligo-affected skin gathers a more focused collection of tumor-related T cells than does blood. They also found that T cells in melanoma tumors are biologically very similar to those in vitiligo-affected skin. With these findings, the team then identified a new subset of “resident memory” cells that have a certain gene profile or "signature." The cells with this signature localize to patient skin and tumor and are found in melanoma tumors from patients who have survived longer than those who don’t have cells with this signature. Turk and Angeles found that T cells that enter tumors have matching clonal partners, or daughter cells, that persist in patient skin and blood up to nine years later.
Findings of this study are newly published in Nature Cancer. No other study has demonstrated cellular evidence of such long-lived immunity to cancer. The extensive collaboration between scientists, surgeons and oncologists required collecting samples of tumor, blood and skin from melanoma patients over a period of several years. Patient specimens were analyzed using state-of-the-art technologies called single-cell RNA sequencing and T-cell receptor sequencing.
These studies were done with a subset of T cells called cytotoxic or “CD8” T cells. Turk and Angeles next want to understand if similar features are seen in patient-helper or “CD4” T cells, and if similar immunity is generated in patients with skin inflammation aside from vitiligo, such as rash. The team will also investigate how different types of immunotherapy affect the new cell population that they discovered.
“Finding that T cells can persist for years throughout skin and blood and understanding what defines such durable immune responses in melanoma patients will lead to better design of therapies to achieve such responses,” says Turk.
Co-leading this work was Christina Angeles, MD, FACS, who designed and led clinical aspects of the study while at NCCC and served as co-corresponding author on the paper. Angeles is now a surgical oncologist at Rogel Cancer Center, University of Michigan.
* * *
Mary Jo Turk, PhD, is the Co-Director of the Immunology and Cancer Immunotherapy Research Program at Dartmouth’s and Dartmouth-Hitchcock’s Norris-Cotton Cancer Center and the O. Ross McIntyre, MD, Endowed Professor and Professor of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth. Her laboratory's immunotherapy research focuses on generating durable memory T cell responses for long-lived immunity to cancer.