Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

Abstract

T-cell-based, personalized immunotherapy can nowadays be considered the mainstream treatment for certain blood cancers, with a high potential for expanding indications. Chimeric antigen receptor T cells (CAR-Ts), an ex vivo genetically modified T-cell therapy product redirected to target an antigen of interest, have achieved unforeseen successes in patients with B-cell hematologic malignancies. Frequently, however, CAR-T cell therapies fail to provide durable responses while they have met with only limited success in treating solid cancers because unique, unaddressed challenges, including poor persistence, impaired trafficking to the tumor, and site penetration through a hostile microenvironment, impede their efficacy. Increasing evidence suggests that CAR-Ts’ in vivo performance is associated with T-cell intrinsic features that may be epigenetically altered or dysregulated. In this review, we focus on the impact of epigenetic regulation on T-cell differentiation, exhaustion, and tumor infiltration and discuss how epigenetic reprogramming may enhance CAR-Ts’ memory phenotype, trafficking, and fitness, contributing to the development of a new generation of potent CAR-T immunotherapies.

Antigen experience history directs distinct functional states of CD8+ CAR T cells during the anti-leukemia response

“…T cell differentiation is a product of epigenetic and transcriptomic state 23 , 27 and while CAR T cells have been extensively profiled post-manufacturing, little work has been done to characterize effects of prior T cell state on post-transduction CAR T cell profiles 5 . We demonstrate that features of these states are maintained through CAR manufacturing and associate with differences in functional profiles.…”

“…Although it has been difficult to track cell fate through the manufacturing process and into patients, previous reports have shown differential function of CAR T cell products generated from memory versus naïve T cells sorted by surface marker phenotypes, which are not always an accurate representation of cellular differentiation state 2 , 3 , 4 . Emerging studies have demonstrated that phenotypic, transcriptomic and epigenomic attributes of the CAR product can influence patient outcomes 5 . During acute infections, naïve CD8+ T cells become activated through the T cell antigen receptor (TCR) by antigen presenting cells displaying cognate antigen and co-stimulatory ligands, and subsequently enter a highly regulated differentiation trajectory.…”

“…Epigenetic modulation of T cells via stimulation through the physiologic TCR has a well-established role in impacting the differentiation program and functional capacity of a pool of antigen-experienced T cells 7 . Emerging data also highlight the importance of epigenetic remodeling in CAR T cell responses to tumors 5 .…”

Apoptosis, a Metabolic “Head-to-Head” between Tumor and T Cells: Implications for Immunotherapy

“…The disruption of the de novo DNA methyltransferase (DNMT3A), which shapes methylation patterns, promotes memory T-cell generation by facilitating demethylation and quicker re-expression of naïve cell-associated genes. Conversely, Tet methycytosine dioxygenase 2, another epigenetic regulator, induces effector cell features by mediating DNA demethylation and the upregulation of effector-associated genes [ 221 ]. At the histone level, CD8 + T-cell subsets display distinctive patterns of histone marks associated with memory T-cell differentiation.…”

Novel insights into cancer stem cells targeting: CAR-T therapy and epigenetic drugs as new pillars in cancer treatment

“…Moreover, epigenetic reprogramming has been used to modulate the differentiation state and to promote the memory phenotypes of CAR-T, to improve CAR-T infiltration and persistence, and finally as an alternative strategy to avoid their exhaustion ( Akbari et al, 2021 ; Alvanou et al, 2023 ).…”