Researchers find cellular evidence behind lasting immune response in some cancer survivors

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Researchers at Norris Cotton Cancer Center have found that resident memory T cells that enter a patient’s skin and blood during immunotherapy are behind the excellent and long-lasting immune responses to cancer that some survivors develop.

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Credit: Shaofeng Yan

LEBANON, NH – Some melanoma patients respond very well to immunotherapy, experiencing profound and durable tumor regression. A fraction of these patients will also develop autoimmunity against their normal melanocytes–the cells that give rise to melanoma–a phenomenon 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 Dartmouth’s and Dartmouth-Hitchcock’s Norris Cotton Cancer Center (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’s and Angeles’ study found that T cells that enter melanoma tumors also have a tendency to enter a patient’s vitiligo-affected skin; that skin accumulates a more focused repertoire of tumor-related T cells than does blood; and that T cells in melanoma tumors are genetically and molecularly very similar to those in vitiligo-affected skin. With these findings, the research team then identified a new subset of “resident memory” (TRM) cells that localize to patient skin and tumor and make high levels of the cytokine interferon gamma. TRM-IFNγ cells have a unique gene expression profile, or “signature,” found in melanoma tumors from patients who have survived longer than those who don’t have the signature. Turk and Angeles found that T cells that infiltrate tumors have matching clonal partners, or daughter cells, that persist in patient skin and blood up to nine years later.

The team’s findings, entitled “Resident and circulating memory T cells persist for years in melanoma patients with durable responses to immunotherapy,” are newly published in Nature Cancer. No prior study has demonstrated cellular evidence of such long-lived immunity to cancer. The extensive collaboration between scientists, surgeons, and oncologists required harvesting tumors, 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.

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Co-leading this work was Christina Angeles, MD, FACS, who designed and led clinical aspects of the study while at NCCC and serves 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.

About Norris Cotton Cancer Center

Norris Cotton Cancer Center, located on the campus of Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH, combines advanced cancer research at Dartmouth College’s Geisel School of Medicine in Hanover, NH with the highest level of high-quality, innovative, personalized, and compassionate patient-centered cancer care at DHMC, as well as at regional, multi-disciplinary locations and partner hospitals throughout NH and VT. NCCC is one of only 51 centers nationwide to earn the National Cancer Institute’s prestigious “Comprehensive Cancer Center” designation, the result of an outstanding collaboration between DHMC, New Hampshire’s only academic medical center, and Dartmouth College. Now entering its fifth decade, NCCC remains committed to excellence, outreach and education, and strives to prevent and cure cancer, enhance survivorship and to promote cancer health equity through its pioneering interdisciplinary research. Each year the NCCC schedules 61,000 appointments seeing nearly 4,000 newly diagnosed patients, and currently offers its patients more than 100 active clinical trials.

About Dartmouth-Hitchcock Health

Dartmouth-Hitchcock Health (D-HH), New Hampshire’s only academic health system and the state’s largest private employer, serves a population of 1.9 million across northern New England. D-H provides access to more than 2,000 providers in almost every area of medicine, delivering care at its flagship hospital, Dartmouth-Hitchcock Medical Center (DHMC) in Lebanon, NH. DHMC was named again in 2020 as the #1 hospital in New Hampshire by U.S. News & World Report, and recognized for high performance in 9 clinical specialties and procedures. Dartmouth-Hitchcock also includes the Norris Cotton Cancer Center, one of only 51 NCI-designated Comprehensive Cancer Centers in the nation; the Children’s Hospital at Dartmouth-Hitchcock, the state’s only children’s hospital; affiliated member hospitals in Lebanon, Keene, and New London, NH, and Windsor, VT, and Visiting Nurse and Hospice for Vermont and New Hampshire; and 24 Dartmouth-Hitchcock clinics that provide ambulatory services across New Hampshire and Vermont. The D-H system trains nearly 400 residents and fellows annually, and performs world-class research, in partnership with the Geisel School of Medicine at Dartmouth and the White River Junction VA Medical Center in White River Junction, VT.

About Geisel School of Medicine at Dartmouth

Founded in 1797, the Geisel School of Medicine at Dartmouth strives to improve the lives of the communities it serves through excellence in learning, discovery, and healing. The Geisel School of Medicine is renowned for its leadership in medical education, healthcare policy and delivery science, biomedical research, global health, and in creating innovations that improve lives worldwide. As one of America’s leading medical schools, Dartmouth’s Geisel School of Medicine is committed to training new generations of diverse leaders who will help solve our most vexing challenges in healthcare.

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Related Journal Article

http://dx.doi.org/10.1038/s43018-021-00180-1

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