how do ion channels and transporters regulate immune system cells, and can they have an effect in immunotherapy?

Ion channels are proteins that allow the permeation of charged ions across the plasma membranes of cells. While they have been studied in other cells, our knowledge of their role in the cells of the immune system is very limited, even though the locations of ion channels on the cell surface make them perfect targets for the purpose of immunotherapy. Dr. Concepcion is particularly interested in the ion channels that transport the cyclic dinucleotide “cGAMP” in T cells within tumors. cGAMP is a potent immune transmitter that, once produced in cells, activates the Stimulator of Interferon Genes (STING) pathway in both the same cell and in neighboring bystander cells. In innate immune cells, when cGAMP binds to STING it leads to the production of type 1 interferons that protect the host against various pathogens and tumorigenic cells. However, STING activation by cGAMP also induces cell cycle arrest and cell death in other immune cells such as T cells, the key mediators of anti-tumor response. Preclinical studies using STING were promising but clinical trials using this pathway have failed, and Dr. Concepcion suggests that this failure might have to do with the dual effect of cGAMP in activating innate immune cells and inhibiting T cell function. With his Young Investigator Award, Dr. Concepcion proposes to target the ion channels that transport cGAMP as a novel approach to stimulate native anti-tumor immune responses by T cells.

Dr. Concepcion has identified LRRC8C as a key component of a particular cGAMP channel and the goal of his project is to establish the role of LRRC8C in anti-tumor immunity and then to identify new cGAMP channels in T cells in the hope of finding new ways to leverage immunotherapy against cancer. He plans to target cGAMP channels in T cells and query their function in the lab as well as studying their potential to inhibit tumor growth in a melanoma mouse model. Additionally, he plans to use CRISPR technology with a single guide RNA library targeting membrane proteins to identify novel cGAMP channels in T cells that can be used as therapeutic targets in anti-tumor immunity. Dr. Concepcion hopes to provide fundamental knowledge about the role of ion channels in T cell mediated immune responses against cancer.