An ion channel that regulates calcium influx into T-cells may be key to improving the outcomes of head and neck cancer patients as well as their responses to immunotherapy, according to a study published in Cancer Research.
The study, “Kv1.3 channels mark functionally competent CD8+ tumor infiltrating lymphocytes in head and neck cancer,” shows that loss of functional Kv1.3 calcium channels in tumor-infiltrating lymphocytes, the cells that fight the tumor, reduce their ability to kill cancer cells in head and neck cancer patients. Therefore, increasing the levels of such receptors in immune cells may enhance immune surveillance in these and possibly other cancer patients.
“Head and neck squamous cell carcinoma is the sixth most common type of cancer, with a five-year survival of 50 percent,” Laura Conforti, PhD, professor in the Department of Internal Medicine at the University of Cincinnati College of Medicine and corresponding author on the study, said in a press release.
“The heterogeneity of these tumors, the complex anatomy of the head and neck region and the proximity of these tumors to several vital organs and structures present a challenge in conventional treatment options of these cancers,” she said.
Immunotherapies that boost patients own immune system have shown promise in the treatment of head and neck cancers. Indeed, the PD-1 inhibitor Keytruda (pembrolizumab) is already approved by the U.S. Food and Drug Administration for this indication, and another PD-1 inhibitor, Opdivo (nivolumab), has yielded promising results in Phase 3 trials.
But these agents only improve the immune system’s ability to recognize cancer cells. If the immune cells are not functioning properly, they won’t be able to effectively eradicate the cancer.
“The extent to which CD8+ cells, a type of T cell capable of killing cancer cells, infiltrate the head and neck tumor affects disease progression and responsiveness to therapy,” Conforti said. “Also, how well CD8+ lymphocytes function within the confines of the tumor microenvironment determines their ability to eradicate cancer cells, and in the case of head and neck solid tumors, tumor infiltrating lymphocytes have multiple functional defects, decreasing their ability to work correctly.”
Researchers knew that CD8-positive T-cells were dependent on their calcium concentration to properly function, and that Kv1.3 ion calcium channels were the main regulators of calcium influx into T-cells. Therefore, they aimed to unveil whether Kv1.3 levels in tumor infiltrating cells could influence patients’ ability to fight cancer.
The team, led by Ameet Chimote, PhD, research associate in the Division of Nephrology and Hypertension, examined tumor samples from 14 head and neck cancer patients to assess how Kv1.3 influenced the function of immune cells within the tumors.
They found that T-cells within the patients’ tumors had a 70 percent reduction in the levels of Kv1.3, compared to T-cells in the blood. This was accompanied by a decrease in calcium ions in the tumor immune cells, which reduced their ability to attack and kill cancer cells.
“Overall our data showed that suppression of Kv1.3 channels in these lymphocytes, the cells that fight off cancer, contribute to their decreased function, raising the possibility that this channel may be used as a potential marker of functionally competent T cells that have infiltrated the tumor mass,” Conforti said.
“These findings are particularly timely as a recently published study in Nature proposes these channels as a potential new target for immunotherapy in cancer. The authors in this study reported that overexpressing these channels in an animal model with cancer lead to increased survival,” she said.
Now, the authors claim that further studies are required to better understand the mechanisms through which Kv1.3 influences head and neck cancers and how to target this pathway to improve patient outcomes.
