Targeting mitochondrial dysfunction in MAIT cells: Potential immunotherapeutic treatment for colorectal cancer

Abstract

Mucosal associated invariant T (MAIT) cells have captured the attention of immunologists and clinicians in recent years due to their abundance in humans, especially in human liver and mucosal tissue. Colorectal cancer is one of the most common forms of cancer in mucosal tissue. Recent evidence reveal activated MAIT cells within the microenvironment of colorectal tumors. The increased tumor infiltration with MAIT cells correlates with poor survival in the colorectal cancer patients, suggesting MAIT cells are promising immunotherapeutic targets in colorectal cancer. Besides well-known role in anti-microbial immunity, MAIT cells have been associated with various forms of cancer. The Th1-biased MAIT cells are proposed to mediate anti-tumor immunity, while IL-17-producing subsets have been implicated in promoting malignancy. Reduced IFN-γ production and elevated IL-17 production of MAIT cells have been found in colorectal tumor tissue and shown to promote tumor growth and metastases. Although the mechanism(s) driving the increase in Th17-biased MAIT cells with reduced IFN-γ production in tumor is not fully understood, recent studies have linked IL-17 response to dysfunctional mitochondria and reactive oxygen species (ROS) from the mitochondria. Therefore, we hypothesize that mitochondrial dysfunction contributes to Th17-skewed MAIT cell responses with decreased IFN-γ production. Mitochondrial targeted antioxidants are supposed to be beneficial for recovering Th1-baised antitumor immunity and inhibiting IL-17 production of MAIT by improving mitochondrial function.