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T Cell Dysfunction and Exhaustion in Cancer.

ABSTRACT: Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. T cell dysfunction induces the out of control of tumors. Recently, T cell dysfunction has been investigated in many experimental and clinical settings. The molecular definition of T cell dysfunction and the underlying causes of the T cell dysfunction has been advanced regardless of the fact that the pathways involved are not well elucidated, which proposing promising therapeutic opportunities in clinic. In this review, we will discuss the recent advances in the molecular mechanisms that affect TME and induce T cell dysfunction, and the development of promising immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction. Better understanding these underlying mechanisms may lead to new strategies to improve the clinical outcome of patients with cancer.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7027373 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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T Cell Dysfunction and Exhaustion in Cancer.

Zhang Zhen Z Liu Shasha S Zhang Bin B Qiao Liang L Zhang Yi Y Zhang Yi Y

Frontiers in cell and developmental biology 20200211

Tumor immunotherapy is a promising therapeutic strategy for patients with advanced cancers. T cells are key mediators of antitumor function that specifically recognize and react to tumor-expressing antigens and have proven critical for cancer immunotherapy. However, T cells are not as effective against cancer as expected. This is partly because T cells enter a dysfunctional or exhausted state, which is characterized by sustained expression of inhibitory receptors and a transcriptional state dist ...[more]

PMID: 32117960

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Project description:T cell-intrinsic regulation, such as anergy, adaptive tolerance and exhaustion, is central to immune regulation. In contrast to Type 1 and Type 17 settings, knowledge of the intrinsic fate and function of Th2 cells in chronic Type 2 immune responses is lacking. We previously showed that Th2 cells develop a PD-1/PD-L2-dependent intrinsically hypo-responsive phenotype during infection with the filarial nematode Litomosoides sigmodontis, denoted by impaired functionality and parasite killing. This study aimed to elucidate the transcriptional changes underlying Th2 cell-intrinsic hypo-responsiveness, and whether it represents a unique and stable state of Th2 cell differentiation. We demonstrated that intrinsically hypo-responsive Th2 cells isolated from L. sigmodontis infected mice stably retained their dysfunctional Th2 phenotype upon transfer to naïve recipients, and had a divergent transcriptional profile to classical Th2 cells isolated prior to hypo-responsiveness and from mice exposed to acute Type 2 stimuli. Hypo-responsive Th2 cells displayed a distinct transcriptional profile to exhausted CD4+ T cells, but upregulated Blimp-1 and the anergy/regulatory-associated transcription factors Egr2 and c-Maf, and shared characteristics with tolerised T cells. Hypo-responsive Th2 cells increased mRNA expression of the soluble regulatory factors Fgl2, Cd38, Spp1, Areg, Metrnl, Lgals3, and Csf1, and a subset developed a T-bet+IFN-?+ Th2/Th1 hybrid phenotype, indicating that they were not functionally inert. Contrasting with their lost ability to produce Th2 cytokines, hypo-responsive Th2 cells gained IL-21 production and IL-21R blockade enhanced resistance to L. sigmodontis. IL-21R blockade also increased the proportion of CD19+PNA+ germinal centre B cells and serum levels of parasite specific IgG1. This indicates a novel regulatory role for IL-21 during filarial infection, both in controlling protection and B cell responses. Thus, Th2 cell-intrinsic hypo-responsiveness is a distinct and stable state of Th2 cell differentiation associated with a switch from a classically active IL-4+IL-5+ Th2 phenotype, to a non-classical dysfunctional and potentially regulatory IL-21+Egr2+c-Maf+Blimp-1+IL-4loIL-5loT-bet+IFN-?+ Th2 phenotype. This divergence towards alternate Th2 phenotypes during chronicity has broad implications for the outcomes and treatment of chronic Type 2-related infections and diseases.

Project description:BackgroundT cells form the major component of anti-tumor immunity. A deeper understanding of T cell exhaustion (TEX) heterogeneity within the tumor microenvironment (TME) is key to overcoming TEX and improving checkpoint blockade immunotherapies in the clinical setting.MethodsWe conducted a comprehensive pan-cancer analysis of TEX subsets from 9564 tumor samples across 30 bulk solid cancer types. Pan-cancer TEX subtypes were identified using literature-derived hierarchical TEX-specific developmental pathway signatures. The potential multi-omics and clinical features involved in TEX heterogeneity were determined.FindingsOur study yielded a dynamic, progressive roadmap and a hierarchical dysfunction landscape regarding TEX within the TME. In total, we identified five pan-cancer TEX subtypes, revealing tissue/cancer type-specific TEX patterns in low immunogenic tumors. By contrast, highly immunogenic tumors tend to harbor high frequencies of progenitor TEX subsets. In addition, the TEX profile also revealed distinct prognoses, intrinsic molecular subtype distribution, immune microenvironment and multi-omics features among the cancers. Network analysis identified four previously unknown TEX-associated cancer genes (tolloid-like 1, myosin heavy chain 111, P2Y receptor family member 8 and protein kinase D2), the possible association with anti-PD-1 immunotherapy response was validated using a single-cell dataset. Finally, a machine learning-based gene signature was developed to model the hierarchical TEX stages, verified in single-cell and immunotherapy patient cohorts.InterpretationOur study provided a TEX-derived system that can be applied for the immune subtyping of cancers and may have implications for the further optimization of personalized cancer immunotherapy.FundingThis study was supported by the National Natural Science Foundation of China (Grant No. 62072341 and 61973240). The funders had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dataset Information

T Cell Dysfunction and Exhaustion in Cancer.

Publications

T Cell Dysfunction and Exhaustion in Cancer.

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