T Cell Dysfunction in Cancer Immunity and Immunotherapy

Abstract

In cancer, T cells become dysfunctional owing to persistent antigen exposure. Dysfunctional T cells are characterized by reduced proliferative capacity, decreased effector function, and overexpression of multiple inhibitory receptors. Due to the presence of various inhibitory signals in the complex tumor microenvironment, tumor-specific T cells have distinct dysfunction states. Therapeutic reactivation of tumor-specific T cells has yielded good results in cancer patients. Here, we review the hallmarks of T cell dysfunction in cancer. Also, we discuss the relationship between T cell dysfunction and cancer immunotherapy.

Keywords: T cell dysfunction; cancer; immunity; immunotherapy; tumor microenvironment.

Figure 1

Classification of dysfunctional T cells.

Figure 2

Inhibitory receptors in dysfunctional T cells. Dysfunctional T cells in the tumor microenvironment (TME) express multiple inhibitory receptors, including PD-1, CTLA-4, Tim-3, LAG-3, and TIGIT. They bind to their respective ligands, which are typically expressed by antigen-presenting cells (APCs) or tumor cells in the TME. PD-1, as the major inhibitory receptor, has two ligands PD-L1 and PD-L2. CTLA-4 can compete with the costimulatory molecule CD28 to bind to CD80 and CD86. Additionally, TIGIT can compete with CD226 to bind to CD112 and CD155. In addition, Tim-3 directly binds to Galectin-9 and CEACAM1 to inhibit T cell function. These inhibitory receptors contribute to T cell dysfunction in cancer.

Figure 3

Traits of T cell dysfunction in cancer. (a) Inhibitory receptors in dysfunctional T cells. One of the traits of dysfunctional T cells is the increased and sustained expression of multiple inhibitory receptors, including PD-1, CTLA-4, Tim-3, LAG-3, and TIGIT. In general, the greater the number of inhibitory receptors coexpressed by dysfunctional T cells, the more severe the dysfunction. (b) Inhibitory cells in the TME. The TME contains various cell types involved in multiple biological processes that promote or inhibit tumor progression. Immunosuppressive cells are present in the TME, which contribute to T cell dysfunction. These inhibitory cells include Treg cells, TAMs, MDSCs, cancer-associated fibroblasts and adipocytes, and endothelial cells. (c) Suppressive soluble mediators. Some soluble molecules exist in the TME and mediate T cell dysfunction. These molecules include IL-10, type I IFNs, IDO, adenosine, VEGF-A, TGF-β, and IL-35. (d) Metabolic pathways in the TME. The activation of T cells and the exertion of antitumor immunity depend on some common metabolic pathways, such as aerobic glycolysis, amino acid metabolism, glutaminolysis, and de novo fatty acid synthesis. These metabolic pathways are also important preconditions for cancer cell proliferation and survival. Hence, within the TME, T cells compete with cancer cells to obtain adequate nutrients. In addition to nutrients, various metabolites are also involved in T cell dysfunction, such as lactic acid, low pH, and hypoxia. (e) Epigenetic imprinting of T cell dysfunction. Epigenetic imprinting of dysfunctional T cells differs from that of effector/memory T cells. Persistent PDCD1 demethylation and unique changes in chromatin accessibility occur in dysfunctional T cells. (f) Transcriptional regulation of T cell dysfunction. Transcriptional regulation of T cell dysfunction involves changes in the expression patterns and transcriptional connection of some important transcription factors, such as T-bet, Eomes, Foxo1, Blimp-1, NFAT, and TOX. TME, tumor microenvironment; Treg cells, regulatory T cells; TAMs, tumor-associated macrophages; MDSCs, myeloid-derived suppressor cells; IDO, indoleamine 2,3-dioxygenase; TGF-β, transforming growth factor-β.