Memory T cell, exhaustion, and tumor immunity

Abstract

CD8 þ T cells are important in protective immunity against intracellular pathogens and tumors. In chronic infections or cancer, CD8 þ T cells are constantly exposed to antigens and inflammatory signals. Such excessive and constitutive signals lead to the deterioration of T cell function, called 'exhaustion'. Exhausted T cells are characterized by low proliferation in response to antigen stimulation, progressive loss of effector function (cytokine production and killing function), expression of multiple inhibitory receptors such as PD-1, Tim3, and LAG3, and metabolic alterations from oxidative phosphorylation to glycolysis. These dysfunctions are associated with altered transcriptional programs and epigenetic regulations and recent studies suggested that NR4a and TOX transcription factors are deeply involved in exhaustion phenotypes. However, an increase the early memory T cells including stem cell memory T (T SCM) cells is critical for T cell persistence and efficient tumor killing especially for adoptive cancer immunotherapy such as CART cell therapy. An increasing amount of evidence supports the therapeutic potential of targeting exhausted T cells and T SCM cells. We have begun to understand the molecular mechanisms of T cell exhaustion and early memory formation, and the clinical application of converting exhausted T cells to rejuvenated early memory T cells is the goal of our study.

Multimodal profiling of lung granulomas reveals cellular correlates of tuberculosis control

“…These cells may represent a "stemlike" population of T cells, which are described as an early differentiating memory phenotype, distinct from naïve T cells, that are long-lived and possess a unique ability to proliferate and self-renew (Ahmed et al, 2016;Caccamo et al, 2018;Gattinoni et al, 2011). Similar cells have been reported in human and animal models of viral infection (Cartwright et al, 2016;Fuertes Marraco et al, 2015) and tumors (Ando et al, 2020;Brummelman et al, 2018;Wu et al, 2019), and in humans with Chagas disease (Mateus et al, 2015). In the tumor microenvironment, stem-like T cells have been described as expressing inhibitory receptors such as PD-1 (Siddiqui et al, 2019).…”

Gene Expression Comparison between Sézary Syndrome and Lymphocytic-Variant Hypereosinophilic Syndrome Refines Biomarkers for Sézary Syndrome

“…The transcription factor TOX is required for the thymic development of all CD4 T-cell lineages [131], while in mature T cells, TOX is upregulated in exhausted T cells in the context of chronic antigen stimulation [132]. Strong TOX staining is observed in lesional skin from a large majority of SS and MF cases, but is much less common in BID skin.…”

Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors

“…Indeed, since checkpoint receptors can be expressed on both effector as well as dysfunctional cells [122], an immunological window needs to be considered to rationalize the lack of ICPi efficiency. A progressive strong expression of immune checkpoint receptors and fixed epigenetic alterations eventually lead to a steady-state inhibition of effector T cells, which cannot be further abrogated by ICPi therapy [11,71,123]. In mouse infection models, only PD-1 int CD44 + but not PD-1 hi CD44 + CD8 T cells were reinvigorated after PD-1/PD-L1 axis blockade [124].…”

“…Their presence was also detected in primary human melanoma [ 65 ]. T SCM are characterized by the phenotype CD45RA + CCR7 + CD62L + typically associated to naïve cells, but they are notably distinguished by their cell surface expression of CD95 and CD122 (also called IL2-Rβ) memory markers, their high amount of stem cell antigen-1 (Sca-1), and TCF1 transcription factor (encoded by Tcf7) expression [ 66 , 67 , 68 , 69 , 70 , 71 ] ( Figure 2 ). In infections and cancers, T SCM express ICPs such as PD-1 or LAG3 but at lower levels than in dysfunctional T cells [ 65 , 71 , 72 ].…”