Abstract
T cell exhaustion has been recognized to play an immunosuppressive role in malignant diseases. Persistent tumor antigen stimulation, the presence of inhibitory immune cells and cytokines in tumor microenvironment (TME), upregulated expression of inhibitory receptors, changes in T cell-related transcription factors, and metabolic factors can all result in T cell exhaustion. Strategies dedicated to preventing or reversing T cell exhaustion are required to reduce the morbidity from cancer and enhance the effectiveness of adoptive cellular immunotherapy. Here, we summarize the current findings of T cell exhaustion in hematological malignancies and chimeric antigen receptor T (CAR-T) immunotherapy, as well as the value of novel technologies, to inverse such dysfunction. Our emerging understanding of T cell exhaustion may be utilized to develop personalized strategies to restore antitumor immunity.
Highlights
T cells recognize tumor antigens expressed by cancer cells and induce tumor rejection in vivo [1]
In context of persistent antigen stimulation, T cells derived in tumor microenvironment (TME) demonstrate the characteristics of exhaustion that leads to a progression towards terminal differentiation [3]
Chimeric antigen receptor T (CAR-T) immunotherapy has been celebrated as a breakthrough due to substantial benefits observed in clinical trials with patients suffering from relapsed or refractory hematological malignancies, such as B cell malignancies and multiple myeloma (MM)
Summary
T cells recognize tumor antigens expressed by cancer cells and induce tumor rejection in vivo [1]. Multiple negative immunoregulatory pathways impede T cellmediated tumor destruction in the tumor microenvironment (TME) [2]. In context of persistent antigen stimulation, T cells derived in TME demonstrate the characteristics of exhaustion that leads to a progression towards terminal differentiation [3]. CAR-T cells prepared from dysfunctional T cells may have weakened targeting and effector functions, as well as obstacles in cell proliferation and persistence in vivo, which may explain the high recurrence rate after CAR-T therapy [3]. We review the hallmarks of exhausted T cells induced in malignant diseases. A better understanding of mechanisms of T cell dysfunction from a fundamental biological perspective will allow optimization for risk stratification and provide novel avenues for the restoration of intratumoral T cell activity
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