Many cancer patients have benefited from the development of anti-cancer immunotherapy drugs known as immune checkpoint inhibitors, but patients with mucosal melanomas—melanomas that occur in the mucous membranes of the head, neck, eyes, respiratory system, and genitourinary region rather than on the skin—are highly resistive to immune checkpoint inhibitors for reasons researchers do not fully understand.
Richard Tobin, PhD, of the University of Colorado Cancer Center, recently obtained a Young Investigator Award from the National Comprehensive Cancer Network (NCCN) to investigate the role of a type of immune cell known as a mucosal-associated invariant T (MAIT) cell in overcoming immunotherapy resistance 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, Surgical Oncology, University of Colorado School of Medicine
Tag team trials
Tobin’s study will be linked to a current clinical trial headed by Theresa Medina, MD, Martin McCarter, MD, and Kasey Couts, PhD, co-director of the CU Center for Rare Melanomas, at the CU Cancer Center.
Their NCCN-funded research is looking at whether decitabine, a hypomethylating agent, together with the immunotherapy drug nivolumab, can help cure mucosal melanomas. Hypomethylating drugs function by reactivating cancer cells’ “turned off” innate immune-sensing pathways, making them less likely to respond to conventional immunotherapy.
While Couts, Medina, and McCarter look into their clinical trial specimens to see if the decitabine-nivolumab combination reactivates immune-sensing pathways, Tobin wants to look into the same samples to check if the drug combination impacts MAIT cell frequency and activation in patients with mucosal melanoma.
Decitabine upregulates a specific protein MR1 that informs the immune system when it recognizes a defect in a cell, which might lead to more successful therapy. The defective cell is killed, while healthy cells in the vicinity are not.
Tobin adds, “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. We also think that the addition of decitabine to nivolumab will enhance treatment efficacy by increasing the frequency and/or activity of MAIT cells.”
Tobin will also use the NCCN award to figure out how MAIT cells contribute to anti-tumor immunity, such as whether they destroy tumor cells directly or indirectly by assisting ordinary T cells in killing 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. If they are acting indirectly, can we modify those interactions between the MAIT cells and the conventional T cells to further promote the activity of those cells?” Tobin notes.
Road to new strategies
If Tobin’s research turns up this theory, cancer specialists may have a new technique to fight mucosal melanomas and other cancers.
Successful completion of this research has the potential to identify MAIT cells as novel regulators of antitumor immunity. 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.”
Richard Tobin, Assistant Research Professor, Surgical Oncology, University of Colorado School of Medicine
Career advancement
Tobin, who works with McCarter, credits the NCCN’s Young Investigator Award for the assistance in moving this research ahead.
It is definitely a big step in my career to get independent funding to work on parts of my research that I am very interested in, and it demonstrates ability to generate ideas that attract funding interest. When I apply for NIH grants, I will have a track record of funding. It is also just a big morale boost moving into the big grant season ahead.”
Richard Tobin, Assistant Research Professor, Surgical Oncology, University of Colorado School of Medicine.
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