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Cancer cells have a clever approach to avoid key immune cells intent on killing them. Researchers from the University of North Carolina Lineberger Comprehensive Cancer Center report in the journal Cancer Immunology Research they have developed a strategy to shut down signals that keep cancer-killing immune cells from infiltrating melanoma.

By blocking receptors on the surface of a certain type of cell, the researchers could increase the number of cytotoxic T-cells – cancer-killing immune cells – that reach melanoma, the deadliest form of skin cancer. Their preclinical studies showed promise for a combination immunotherapy strategy, increasing median survival and slowing tumor growth in laboratory models.

Shelton Earp, MD, and Alisha Holtzhausen, PhD

“We found that a family of receptors expressed on the surface of immature immune cells can regulate a whole immunosuppressive pathway,” said Alisha Holtzhausen, PhD, postdoctoral research associate at UNC Lineberger. “By inhibiting the signaling pathway of these cells, we can stop the suppression of these cells, and that allows for more cytotoxic T-cells to come in and kill the tumor. And if we pair that strategy with standard-of-care immunotherapy, we get a better response and increased survival.”

Immunotherapy treatments known as checkpoint inhibitors have improved the outlook for advanced melanoma and other cancers, but researchers say there’s room for further improvement. Checkpoint inhibitors work by “releasing the brakes” on cytotoxic T-cells. These brakes are important because they prevent immune cells from attacking normal, healthy cells, but cancer cells can use the same braking mechanism to hide from the immune system. Researchers want to improve patients’ response rates to these drugs as well as their overall survival rates.

In their recent study, researchers investigated the role of a different part of the immune system, the innate immune system, in suppressing the response of cancer-fighting T-cells. They assessed whether the innate immune system plays a role in keeping cytotoxic T-cells from tumor cells.

They found that a certain type of innate immune cell, called myeloid-derived suppressor cells, can increase the expression of TYRO3, AXL and MERTK receptors on their surface. Collectively known as TAM RTKs, these receptors trigger a cascade of secretions that stop the tumor-fighting T cells from growing and dampen the overall immune response.

Using an experimental drug called UNC4241 made in the lab of Xiaodang Wang, PhD, member of UNC Lineberger and research associate professor in the UNC Eshelman School of Pharmacy, and Stephen Frye, PhD, member of UNC Lineberger and Fred Eshelman Distinguished Professor in the UNC Eshelman School of Pharmacy, researchers blocked TYRO3, AXL and MERTK activity. Their preclinical studies showed that they could slow tumor growth and increase numbers of cytotoxic T-cells within tumors. When combined with commonly used immune checkpoint inhibitors, survival was even further prolonged.

“By inhibiting the function of the TAM RTKs with a drug made by our collaborators, UNC4241, we can stop myeloid-derived suppressor cells from being suppressive, resulting in a more robust anti-tumor immune response and thereby decreasing tumor growth,” Holtzhausen said.

Importantly, they found that patients with metastatic melanoma exhibited an increase in circulating MERTK-positive suppressive cells.

“Remarkable advances have been made in a subset of human cancers through the use of new T cell-directed immune checkpoint inhibitors,” said Shelton Earp, MD, director of UNC Lineberger, Lineberger Professor of Cancer Research and the paper’s senior author. “Our work, and that of others, show that we need to pay more attention to the ‘front line’ of the immune system — innate immune cells. We believe that MERTK signaling, in part, controls the natural anti-inflammatory signaling in this system that prevents auto-immunity. However, inside a patient’s tumor, these signals are subverted to cloak the tumor from immune destruction. This work is one step in the right direction to get both limbs of the immune system focused on eliminating cancer.”

In addition to Holtzhausen, other authors included William Harris, Eric Ubil, Debra M. Hunter, Jichen Zhao, Yuewei Zhang, Dehui Zhang, Qingyang Liu, Xiaodong Wang, Douglas K. Graham, Stephen V. Frye, and H. Shelton Earp.

The study was supported by the American Cancer Society, the National Institutes of Health, Saban Family Foundation Team Science Award from the Melanoma Alliance, and the Breast Cancer Research Foundation.

Conflict of interest: Earp, Frye and Graham are founders and board members of a UNC start-up company, Meryx, which has licensed UNC patents. Along with Wang and D. Zhang, they have an equity interest in Meryx, which is developing inhibitors for the TAM RTK family. UNC4241 was provided by the academic labs of Frye and X. Wang.