TAMPA, Fla. (Nov. 1, 2019) - Immunotherapy has become a standard treatment approach for several types of cancer, including melanoma. However, tumors can escape immune cell detection even with the use of immunotherapies. In a new study published in Cancer Immunology Research, Moffitt Cancer Center researchers, in collaboration with the University of Miami's Miller School of Medicine, describe a cellular mechanism that controls tumor cell recognition by immune cells.
Agents that activate the immune system in advanced melanoma have significantly improved outcomes, and many patients have long-term responses following immunotherapy treatment. However, according to James Mulé, Ph.D., associate center director of Translational Science at Moffitt, "There remains a subset of melanoma patients treated with immune-based therapies who do not achieve clinical benefit. Understanding the mechanisms underlying both successful and failed immune responses may help improve immunotherapeutic approaches."
Moffitt researchers believe that one reason why patients may not respond well to immunotherapies is because their immune system does not recognize tumor cells properly. They hypothesized that the STING protein signaling pathway may be a contributing factor to immune cell recognition.
The STING pathway is known to contribute to the activation of the immune system by stimulating the production of protein messengers called interferons. Defects in STING signaling have been reported in several different types of cancer, including melanoma; however, the impact of these defects is unclear. In order to improve our understanding of how defects in STING signaling may contribute to cancer, the Moffitt team conducted a series of laboratory experiments in human melanoma cell lines.
The researchers discovered that there are many human melanoma cell lines that have completely lost expression of STING and do not respond to signaling that activates the pathway. They also found that some human melanoma cell lines maintain STING expression, but are still incapable of activating the signaling pathway. This suggests that an unknown alternative mechanism may also be responsible for defects in STING signaling, other than loss of STING expression itself.
In order to determine how STING signaling functions under normal circumstances, the researchers conducted experiments in human melanoma cell lines that express a functional STING pathway. They discovered that activation of STING results in production of the molecular messengers interferon-beta and CXCL10 that stimulate inflammation and an immune response. Activation of STING also caused human melanoma cells to increase the expression level of proteins called MHC molecules on their cell surface that allow them to be recognized and targeted by immune cells called T cells. Conversely, human melanoma cells that had dysfunctional STING signaling were much less able to be recognized by T cells.
These observations suggest that one mechanism by which tumor cells bypass immune detection may be through alterations in the STING pathway. The researchers hope that their work will lead to an improved understanding of immune cell activation and better treatment approaches for patients. "Further understanding of the regulation and function of STING in melanomas and other tumor types may lead to the development of strategies that target the STING pathway to improve the efficacy of adoptive cell therapy and other immunotherapies in patients who do not currently benefit from these interventions," said Mulé.
The study was supported by funds from the National Cancer Institute (R01 CA148995, R01 CA184845, P30 CA076292 and P50 CA168536), the Cindy and Jon Gruden Fund, the Chris Sullivan Fund, the V Foundation, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
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Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's scientific excellence, multidisciplinary research, and robust training and education. Moffitt is a Top 10 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt devotes more than 2 million square feet to research and patient care. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 6,000 team members, Moffitt has an economic impact in the state of $2.5 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter and YouTube.