Chemogenetically engineered macrophage for phenotype modulation

Abstract

Adoptive cell transfer (ACT) is a method to separate immune cells such as T cell, differentiate and activate them ex vivo, and injecting them back into the body. Macrophages can directly kill cancer cells through phagocytosis and secrete different pro-inflammatory cytokines. However, due to the highly plastic property, macrophages can be changed to anti-inflammatory phenotype in immune suppressive environment. Previous studies have not taken into consideration phenotype change of macrophages. Therefore, a new method should be developed to maintain pro-inflammatory phenotype of macrophage even in immune suppressive tumor microenvironment. This study proposes chemogenetically engineered macrophage to solve the problem. Chemogenetics use a G-protein coupled receptor that responds to clozapine-N-oxide. When the receptor is activated, macrophages can be induced into pro-inflammatory phenotype by increasing intracellular calcium ion concentration. Using this technology, macrophages are specifically controlled by CNO, and activation can be induced even in a TME environment. In addition, side effects such as cytokine release syndrome due to excessive inflammation can be prevented.