Posted October 11, 2019

Yana Najjar, M.D., University of Pittsburgh
Greg Delgoffe, Ph.D., University of Pittsburgh

Melanoma is the second most common diagnosed cancer in active duty Service members.¹ This is likely due to increased sun exposure from prolonged periods outdoors during periods of deployment. In the last 10 years, immunotherapy, a type of cancer treatment that stimulates the immune system, has shown efficacy in treating advanced melanoma and significantly prolonging life. One type of immunotherapy, called checkpoint inhibition, targets inhibitory proteins expressed on T cells with the goal of activating anti-tumor functions. Despite the successes of immunotherapy, it is not effective for every patient. Drs. Yana Najjar and Greg Delgoffe, with a FY17 Translational Team Science Award, will investigate why some patients do not respond to immunotherapy.  

Dr. Delgoffe’s group had previously shown that metformin, a diabetes drug that regulates blood glucose levels, improves oxygen and glucose availability to T cells, and therefore promotes anti-tumor activity. As the tumor microenvironment is nutrient- and oxygen-deprived, it limits the ability of T cells to attack and kill tumor cells.  Dr. Najjar, a melanoma oncologist, is taking these findings to the clinic, to try and improve immunotherapy treatments. Drs. Najjar and Delgoffe hypothesize that the combination of the checkpoint inhibitor programmed death protein 1 (PD-1) and metformin may lead to increased T cell activation and proliferation, therefore increasing the T cells’ ability to kill tumor cells. T cells will be collected from patients with advanced melanoma before and after treatment. Tumor-infiltrating T cells and peripheral blood T cells will be profiled for markers of immune cell function and exhaustion as well as sequenced to analyze gene expression before and after treatment. Results from this study will advance the understanding of how the tumor microenvironment impacts the activity of T cells and how to manipulate metabolism to overcome this barrier to activating the body’s own immune system to fight melanoma.

 

Reference:

¹ Lee T, Williams VF, Taubman SB, and Clark LL. 2016. Incident Diagnoses of Cancers in the Active Component and Cancer-Related Deaths in the Active and Reserve Components, U.S. Armed Forces, 2005–2014. Military Surveillance Monthly Report. 23(7):23-31.

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