Next generation immunotherapy: enhancing stemness of polyclonal T cells to improve anti-tumor activity

Kishton, Rigel J.; Vodnala, Suman K.; Vizcardo, Raul; Restifo, Nicholas P.

doi:10.1016/j.coi.2021.10.001

Cited by 16 publications

(8 citation statements)

References 60 publications

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“…Although great success has been achieved in treating hematopoietic malignancies [ 26 , 35 ], very rare patients with solid tumors acquire durable benefits from this therapy [ 36 ]. One reason accounting for the failure of CAR-T therapy is the differentiation of T cells into terminal effectors during expansion, which lack stemness and are incapable to persist in vivo after adoptive transfer [ 37 , 38 ]. Our data showed that chemical inhibition of histone acetylation with C646 during T cell expansion limited effector functions of T cells, preserving them in less differentiated state.…”

Section: Discussionmentioning

confidence: 99%

Per-cell histone acetylation is associated with terminal differentiation in human T cells

Yang,

Li,

et al. 2024

Clin Epigenet

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Background Epigenetic remodeling at effector gene loci has been reported to be critical in regulating T cell differentiation and function. However, efforts to investigate underlying epigenetic mechanisms that control T cell behaviors have been largely hindered by very limited experimental tools, especially in humans. Results In this study, we employed a flow cytometric assay to analyze histone acetylation at single-cell level in human T cells. The data showed that histone acetylation was increased during T cell activation. Among T cell subsets, terminally differentiated effector memory T (TEMRA) cells robustly producing effector cytokines were hyper-acetylated. Conversely, these TEMRA cells had lower expression levels of TCF-1, a key transcription factor for maintaining stem cell features. Pharmaceutical inhibition of histone acetylation using a small molecule C646 restrained the production of effector molecules, but retained stem cell-like properties in T cells after expansion. Conclusions Per-cell histone acetylation is associated with terminal differentiation and poor stemness in human T cells. These observations suggest a new approach to enhance the stem cell-like properties of T cells and improve the efficacy of immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Per-cell histone acetylation is associated with terminal differentiation in human T cells

Yang,

Li,

et al. 2024

Clin Epigenet

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“…An understanding of strategies that might be used to enhance stem cell-like features is critical for the success of adoptive T cell therapies used for many types of cancers. 33,34 While effector cells are efficient at producing cytokine in vitro, they do not persist after adoptive transfer and ultimately fail to control the tumor. 35 Strong response to therapy correlates with the abundance of stem cells in the transferred cell pool.…”

Section: Discussionmentioning

confidence: 99%

CD8 agonism functionally activates memory T cells and enhances antitumor immunity

Madi

Weisshaar

Buettner

et al. 2022

Intl Journal of Cancer

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Memory CD8+ T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8+ T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody‐mediated activation of memory CD8+ T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell‐mediated cytotoxicity and promoted effector cytokine production in a glucose‐ and glutamine‐dependent manner. Furthermore, pretreatment of memory CD8+ T cells with an agonistic anti‐CD8 antibody enhanced their tumoricidal activity in vitro and in vivo. From these studies, we conclude that CD8 agonism activates glucose and glutamine metabolism in memory T cells and enhances the efficacy of memory T cell‐based cancer immunotherapy.

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“…In natural immune responses, activated T cells not only have different phenotypes, but they also originate from different T‐cell clones carrying different TCRs 101 . This is also the case in the context of anticancer immunity, where multiple clones react to several tumor‐associated antigens 102 to launch an efficient response. Many approaches in cancer immunotherapy, from vaccines to adoptive cell transfer, are trying to harness the antitumor potential of these polyclonal T‐cell populations 103 …”

Section: Future Directions For Immune Cell Engineeringmentioning

confidence: 99%

A synthetic biology approach to engineering circuits in immune cells

Hoces

Miguens‐Blanco

Hernández-López

2023

Immunological Reviews

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SummaryA synthetic circuit in a biological system involves the designed assembly of genetic elements, biomolecules, or cells to create a defined function. These circuits are central in synthetic biology, enabling the reprogramming of cellular behavior and the engineering of cells with customized responses. In cancer therapeutics, engineering T cells with circuits have the potential to overcome the challenges of current approaches, for example, by allowing specific recognition and killing of cancer cells. Recent advances also facilitate engineering integrated circuits for the controlled release of therapeutic molecules at specified locations, for example, in a solid tumor. In this review, we discuss recent strategies and applications of synthetic receptor circuits aimed at enhancing immune cell functions for cancer immunotherapy. We begin by introducing the concept of circuits in networks at the molecular and cellular scales and provide an analysis of the development and implementation of several synthetic circuits in T cells that have the goal to overcome current challenges in cancer immunotherapy. These include specific targeting of cancer cells, increased T‐cell proliferation, and persistence in the tumor microenvironment. By harnessing the power of synthetic biology, and the characteristics of certain circuit architectures, it is now possible to engineer a new generation of immune cells that recognize cancer cells, while minimizing off‐target toxicities. We specifically discuss T‐cell circuits for antigen density sensing. These circuits allow targeting of solid tumors that share antigens with normal tissues. Additionally, we explore designs for synthetic circuits that could control T‐cell differentiation or T‐cell fate as well as the concept of synthetic multicellular circuits that leverage cellular communication and division of labor to achieve improved therapeutic efficacy. As our understanding of cell biology expands and novel tools for genome, protein, and cell engineering are developed, we anticipate further innovative approaches to emerge in the design and engineering of circuits in immune cells.

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Next generation immunotherapy: enhancing stemness of polyclonal T cells to improve anti-tumor activity

Cited by 16 publications

References 60 publications

Per-cell histone acetylation is associated with terminal differentiation in human T cells

Per-cell histone acetylation is associated with terminal differentiation in human T cells

CD8 agonism functionally activates memory T cells and enhances antitumor immunity

A synthetic biology approach to engineering circuits in immune cells

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