Research progress on targetingmetabolic reprogramming of tumormicroenvironment to reinvigorate exhausted CD8+T cells

Abstract

CD8+T cell exhaustion is one of the most important reasons for the low response rate of immunotherapy. In the tumor microenvironment(TME), tumor cells preferentially utilize metabolic reprogramming such as aerobic glycolysis to get an advantage on survival. Yet tumour-infiltrating immune cells typically experience metabolic stress, which causes hypoxia, consumption of nutrients, and accumulation of waste products and so on, resulting in the dysregulation on T cell differentiation and may have some impact on the production of exhausted CD8+T cells. Emerging evidence has shown that exhausted CD8+T cells progressively develop metabolic insufficiency with altered signaling cascades and epigenetic programs, which eventually act as a barrier to effective immunotherapies and lead to poor response to immune checkpoint blockade therapy. So a better understanding of the metabolic changes of exhausted CD8+T cells with impaired function, as well as the metabolic interactions between CD8+T cell and tumor cell in the TME, can provide more opportunities for combining metabolic intervention with immunotherapy so as to reverse CD8+T cell exhaustion and restore their anti-tumor activity. Here, in this review, we would like to focus on the metabolic characteristics of CD8+ exhausted T cells and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

Keywords

• exhausted cd8+t cell
• cd8+tumor infiltrating lymphocytes(cd8+tils)
• metabolic competition