A potential way for overcoming immunotherapy resistance in patients with mucosal melanomas

The development of the anti-cancer immunotherapy drugs called immune checkpoint inhibitors has improved treatment for many cancer patients, but patients with mucosal melanomas -; melanomas that occur not on the skin but in the mucous membranes in the head, neck, eyes, respiratory tract, and genitourinary region -; are particularly resistant to immune checkpoint inhibitors for reasons researchers don't fully understand.

University of Colorado (CU) Cancer Center member Richard Tobin, PhD, recently received a Young Investigator Award from the National Comprehensive Cancer Network (NCCN) to study the role of a certain type of immune cell called a mucosal-associated invariant T (MAIT) cell in overcoming resistance to immunotherapy in patients with mucosal melanomas.

MAIT cells are a newly described population of T cells that are not very well defined in the context of cancer. We have had an initial publication showing that the frequency of MAIT cells in cutaneous melanoma patients is positively correlated with responses to immunotherapy."

Richard Tobin, assistant research professor of surgical oncology. University of Colorado School of Medicine

Tag team trials

Tobin will tie his research to a current clinical trial led by CU Cancer Center members Martin McCarter, MD, Theresa Medina, MD, and Kasey Couts, PhD, co-director of the CU Center for Rare Melanomas. Their NCCN-funded study is investigating whether a hypomethylating agent called decitabine, used in conjunction with the immunotherapy drug nivolumab, might aid in treatment of mucosal melanomas. Hypomethylating agents work by re-activating innate immune-sensing pathways that are "turned off" by cancer cells, making them less likely to respond to standard immunotherapy.

While Couts, Medina, and McCarter investigate their clinical trial samples to see if the decitabine-nivolumab combo reactivates immune-sensing pathways, Tobin plans to further investigate the same samples to see if the drug combination affects MAIT cell frequency and activation in mucosal melanoma patients. The study could lead to especially effective treatment as decitabine upregulates a protein called MR1 that signals the immune system when it detects a defect in a cell. The defective cell is destroyed, but nearby healthy cells are left untouched.

"We hypothesize that MAIT cells directly participate in antitumor immunity and that upregulation of MR1 by decitabine will enhance the killing capacity of MAIT cells and improve clinical outcomes for mucosal melanoma patients," Tobin says. "We also think that the addition of decitabine to nivolumab will enhance treatment efficacy by increasing the frequency and/or activity of MAIT cells."

The NCCN grant also will help Tobin determine how MAIT cells participate in anti-tumor immunity: whether they kill tumor cells directly or act indirectly by helping conventional T cells to kill tumor cells.

"A future research direction would be to look at what recruits MAIT cells to tumors, and if we can use that to further enhance the efficacy of immunotherapies," he says. "If they're acting indirectly, can we modify those interactions between the MAIT cells and the conventional T cells to further promote the activity of those cells?"

Road to new strategies

If Tobin's research proves his hypothesis, cancer doctors could have another tool to treat mucosal melanomas and similar cancers.

"Successful completion of this research has the potential to identify MAIT cells as novel regulators of antitumor immunity," he says. "The knowledge gained in this study will identify new therapeutic strategies to enhance the efficacy of current and next-generation immune checkpoint inhibitors in mucosal melanoma and other hard-to-treat tumors."

Career advancement

Tobin, who collaborates with McCarter, says he's grateful to the NCCN for the Young Investigator Award for helping him move his independent research forward.

"It's definitely a big step in my career to get independent funding to work on parts of my research that I'm very interested in, and it demonstrates ability to generate ideas that attract funding interest," he says. "When I apply for NIH grants, I will have a track record of funding. It's also just a big morale boost moving into the big grant season ahead."

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