Bone marrow microenvironment signatures associate with patient survival after guadecitabine and atezolizumab therapy in HMA-resistant MDS.

Almost 50% of patients with myelodysplastic syndrome (MDS) are refractory to first-line hypomethylating agents (HMAs), which presents a significant clinical challenge considering the lack of options for salvage. Past work revealed that immune checkpoint molecules on peripheral myeloblasts and immune cells are up-regulated after HMA treatment. Therefore, we conducted a Phase I/II clinical trial combining guadecitabine (an HMA) and atezolizumab (an immune checkpoint inhibitor) to treat HMA-relapsed or refractory (HMA-R/R) MDS patients.

Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.

Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy.

T cell dysfunction and therapeutic intervention in cancer.

Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells.

Conserved epigenetic hallmarks of T cell aging during immunity and malignancy.

Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such 'epigenetic clocks' appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue 'counting' beyond species lifespan.

Cellular and molecular waypoints along the path of T cell exhaustion.

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.

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion.

Regulatory T cell (Treg) therapy is a promising approach to improve outcomes in transplantation and autoimmunity. In conventional T cell therapy, chronic stimulation can result in poor in vivo function, a phenomenon termed exhaustion. Whether or not Tregs are also susceptible to exhaustion, and if so, if this would limit their therapeutic effect, was unknown.

T cell TET2 disruption cuts the breaks on antitumor CAR T cell therapy.

Functional persistence of chimeric antigen receptor (CAR) T cells is required for sustaining an antitumor response. Recently, Jain et al. revealed that disruption of TET2 in CAR T cells resulted in antigen-independent CAR T cell hyperproliferation that enhanced tumor control in mice, highlighting the potential of epigenetic strategies to improve T cell-based cancer immunotherapy.

Tapping the keg of discovery to advance T cell therapy.

Starting on 19 September 2022, the very first ImmunOctoberfest conference took place in Raitenhaslach, Germany, bringing together scientists from all over the world to discuss ‘bridging innovation and translation in T cell immunotherapy’.

Improving antitumor T cells.

Disrupting cell cycle regulators can overcome anticancer T cell dysfunction.

Mechanisms of T cell exhaustion guiding next-generation immunotherapy.

The functional decline in T cells during their chronic stimulation, commonly referred to as T cell exhaustion, is a major limitation for current immunotherapy approaches. As modern medicine embraces therapeutic approaches that exploit the immuno-oncology interface, a primary question is how is T cell function maintained over time in scenarios of prolonged tumor burden. Deciphering the molecular mechanisms of T cell exhaustion is now enabling the field to begin using cardinal features of T cell differentiation to develop biomarkers that can delineate responders from nonresponders prior to treatment with T cell-based therapeutics.

CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia.

CD19-CAR T cell therapy has evolved into the standard of care for relapsed/refractory B cell acute lymphoblastic leukemia (ALL); however, limited persistence of the CAR T cells enables tumor relapse for many patients. To gain a deeper understanding of the molecular characteristics associated with CAR T cell differentiation, we performed longitudinal genome-wide DNA methylation profiling of CD8 CD19-CAR T cells post-infusion in ALL patients. We report that CAR T cells undergo a rapid and broad erasure of repressive DNA methylation reprograms at effector-associated genes.

Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.

Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined.

Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation.

To gain insight into the signaling determinants of effector-associated DNA methylation programming among CD8 T cells, we explore the role of interleukin (IL)-12 in the imprinting of IFNg expression during CD8 T cell priming. We observe that anti-CD3/CD28-mediated stimulation of human naive CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promoter. However, anti-CD3/CD28 stimulation in the presence of the inflammatory cytokine, IL-12, results in stable demethylation of the IFNg locus that is commensurate with IFNg expression.

CAR T cells need a pitstop to win the race.

Prolonged TCR-driven stimulation can induce a dysfunctional T cell state, broadly described as T cell exhaustion, limiting the clinical potential of chimeric antigen receptor (CAR) T cells. Recent findings in Science indicate that early cessation of CAR T cell tonic signaling can prevent stabilization of exhaustion-associated epigenetic programs, enabling a prolonged anti-tumor response.

Defining the Molecular Hallmarks of T-Cell Memory.

The pool of memory CD8 T cells is comprised of highly specialized subpopulations of cells with both shared and distinct functions. The ongoing study of T-cell memory is focused on how these different subpopulations arise, how the cells are maintained over the life of the host, and how the cells protect a host against reinfection. As a field we have used the convenience of a narrow range of surface markers to define and study these memory T-cell subsets.

Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL.

Chimeric antigen receptor (CAR)-T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T-cell expansion and memory-like cell formation.

Rewriting History: Epigenetic Reprogramming of CD8 T Cell Differentiation to Enhance Immunotherapy.

The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8 T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade.

Beta cell-specific CD8 T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes.

The pool of beta cell-specific CD8 T cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell 'multipotency index' and found that beta cell-specific CD8 T cells retained a stem-like epigenetic multipotency score. Single-cell assay for transposase-accessible chromatin using sequencing confirmed the coexistence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8 T cells.

Developmental plasticity allows outside-in immune responses by resident memory T cells.

Central memory T (T) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (T) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated T cells rejoined the circulating pool.

Epigenetic Maintenance of Acquired Gene Expression Programs during Memory CD8 T Cell Homeostasis.

Memory CD8 T cells have a unique ability to provide lifelong immunity against pathogens containing their cognate epitope. Because of their ability to provide lifelong protection, the generation of memory T cells is now a major focus for current vaccination or adoptive cell therapy approaches to treat chronic viral infections and cancer. It is now clear that maintenance of memory CD8 T cells occurs through a process of antigen-independent homeostatic proliferation, which is regulated in part by the gamma chain cytokines IL-7 and IL-15.

Homeostatic Proliferation of Human CD8 T Cells.

Long-lived T-cell-mediated immunity requires persistence of memory T cells in an antigen-free environment while also maintaining a heightened capacity to recall effector functions. Such antigen-independent homeostatic proliferation is mediated in part by the common gamma-chain cytokines IL-7 and IL-15. To further explore the mechanisms governing maintenance of effector functions in long-lived memory T cells during antigen-independent proliferation, human naïve and memory CD8 T cells can be sorted from peripheral blood mononuclear cells (PBMCs), labeled with the proliferation-tracking dye carboxyfluorescein succinimidyl ester (CFSE), and then purified based on their levels of cell division.

Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis.

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T), and longer-lived central memory (T) and stem cell memory (T) CD8 T cells identified effector molecules with demethylated promoters and poised for expression.