T cell responses must be balanced to ensure adequate protection against malignant transformation and an array of pathogens while also limiting damage to healthy cells and preventing autoimmunity. T cell exhaustion serves as a regulatory mechanism to limit the activity and effector function of T cells undergoing chronic antigen stimulation. Exhausted T cells exhibit poor proliferative potential; high inhibitory receptor expression; altered transcriptome, epigenome, and metabolism; and, most importantly, reduced effector function. While exhaustion helps to restrain damage caused by aberrant T cells in settings of autoimmune disease, it also limits the ability of cells to respond against persistent infection and cancer, leading to disease progression. Here we review the process of T cell exhaustion, detailing the key characteristics and drivers as well as highlighting our current understanding of the underlying transcriptional and epigenetic programming. We also discuss how exhaustion can be targeted to enhance T cell functionality in cancer. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

T Cell Exhaustion.

Overcoming CD8+ T cell exhaustion is critical in cancer immunotherapy. Recently, an intratumor stem/progenitor-like CD8+ T cell (Tprog cell) population that mediates the persistence of antitumor responses has been defined, which can further develop into a terminally differentiated CD8+ T cell (Tterm cell) subpopulation with potent cytotoxic functions. Tprog cells are the main responders to immune checkpoint blockade therapies, yet how extrinsic signals via transcription factors control Tprog cell generation and persistence in tumors is unclear. Here, we found that BCL6 inhibits tumor-specific Tterm cell generation from Tprog cell downstream of TCF1. We show that Bcl6 deficiency reduced the persistence of Tprog cells, without affecting their generation, thus abrogating long-term tumor control. High-level BCL6 expression was observed in tumor-specific T cells in draining lymph nodes (LNs) and was associated with T cell exhaustion. This was observed in TOX+TCF1+ Tprog cells in both LNs and tumors. BCL6 expression in CD8+ T cells was up-regulated by TGF-β–SMAD2 signaling but down-regulated by the IL-2–STAT5 pathway. Mechanistically, BCL6 transcriptionally repressed the expression of Tterm cell–associated genes and induced those of Tprog cell–related genes, in a manner antagonistic to BLIMP1. Prdm1 deficiency also promoted the Tprog cell program and greatly improved the efficacy of anti–PD-1 therapy. Thus, we identified the TGF-β–BCL6 and IL-2–BLIMP1 antagonistic pathways in regulation of antitumor CD8+ T cells, which may benefit the development of long-lasting and effective cancer immunotherapy. Description BCL6 and BLIMP1 antagonistically regulate antitumor CD8+ exhausted T cells. Editor’s summary Intratumoral exhausted CD8+ stem- or progenitor-like (Tprog) and terminally differentiated (Tterm) cells mediate antitumor immunity and response to immunotherapy. Sun et al. investigated how exhausted CD8+ T cells are transcriptionally regulated in murine tumor models, identifying that the transcription factors BCL6 and BLIMP1 reciprocally regulate Tprog and Tterm cell fates, respectively. BCL6 promoted the long-term persistence of Tprog cells in response to TGF-β–SMAD2 signaling by repressing the Tterm transcriptional program. Conversely, IL-2–STAT5 signaling repressed BCL6, resulting in BLIMP1 transcription and subsequent Tterm differentiation. Furthermore, Prdm1 deficiency in tumor-specific CD8+ T cells improved the efficacy of anti–PD-1. Together, these findings identify a regulatory network that controls CD8+ T cell exhaustion in cancer, which could be targeted to alter the balance of Tprog and Tterm cells and improve responses to immunotherapy. —Hannah Isles

BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1

Thirty years of foundational research investigating molecular and cellular mechanisms promoting T cell exhaustion are now enabling rational design of T cell–based therapies for the treatment of chronic infections and cancer. Once described as a static cell fate, it is now well appreciated that the developmental path toward exhaustion is composed of a heterogeneous pool of cells with varying degrees of effector potential that ultimately converge on a terminally differentiated state. Recent description of the developmental stages along the differentiation trajectory of T cell exhaustion has provided insight into past immunotherapeutic success and future opportunities. Here, we discuss the hallmarks of distinct developmental stages occurring along the path to T cell dysfunction and the impact of these discrete CD8+ T cell fates on cancer immunotherapy. Description Defining discrete cellular subsets of T cell exhaustion is enabling new approaches for improving T cell–based immunotherapies.

Cellular and molecular waypoints along the path of T cell exhaustion

Abstract Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis. 

Pre-metastatic niche: formation, characteristics and therapeutic implication

mRNA delivery has shown high application value in the treatment of various diseases, but its effective delivery is still a major challenge at present. Herein, we propose a lantern-shaped flexible RNA origami for mRNA delivery. The origami is composed of a target mRNA scaffold and only two customized RGD-modified circular RNA staples, which can compress the mRNA into nanoscale and facilitate its endocytosis by cells. In parallel, the flexible structure of the lantern-shaped origami allows large regions of the mRNA to be exposed and translated, exhibiting a good balance between endocytosis and translation efficiency. The application of lantern-shaped flexible RNA origami in the context of the tumor suppressor gene, Smad4 in colorectal cancer models demonstrates promising potential for accurate manipulation of protein levels in in vitro and in vivo settings. This flexible origami strategy provides a competitive delivery method for mRNA-based therapies. 

/pdf/lantern-shaped-flexible-rna-origami-for-smad4-mrna-delivery-16wub6ha.pdf

Lantern-shaped flexible RNA origami for Smad4 mRNA delivery and growth suppression of colorectal cancer

In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remains not well understood. Here, we found that STAT3 signaling plays essential roles in promoting intratumor Texterm cell development by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while it suppresses those expressed by the progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at the effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits the development of more effective immunotherapies against tumors.

STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection.

Transforming growth factor–β is well known to restrain cytotoxic T cell responses to maintain self-tolerance and to promote tumor immune evasion. In this study, we have investigated the role of SMAD4, a core component in the TGF-β signaling pathway, in CD8+ T cells. Unexpectedly, we found that SMAD4 was critical in promoting CD8+ T cell function in both tumor and infection models. SMAD4-mediated transcriptional regulation of CD8+ T cell activation and cytotoxicity was dependent on the T cell receptor (TCR) but not TGF-β signaling pathway. Following TCR activation, SMAD4 translocated into the nucleus, up-regulated genes encoding TCR signaling components and cytotoxic molecules in CD8+ T cells and thus reinforced T cell function. Biochemically, SMAD4 was directly phosphorylated by ERK at Ser367 residue following TCR activation. Our study thus demonstrates a critical yet unexpected role of SMAD4 in promoting CD8+ T cell–mediated cytotoxic immunity.

SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8+ T cell cytotoxic function

https://doi.org/10.1016/j.isci.2023.106221

Chidamide suppresses adipogenic differentiation of bone marrow derived mesenchymal stem cells via increasing REEP2 expression

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STAT3 regulates CD8+ T cell differentiation and functions in cancer and acute infection.

BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1

SMAD4, activated by the TCR-triggered MEK/ERK signaling pathway, critically regulates CD8+ T cell cytotoxic function

Chidamide suppresses adipogenic differentiation of bone marrow derived mesenchymal stem cells via increasing REEP2 expression