Cell-Intrinsic Barriers of T Cell-Based Immunotherapy - PubMed (original) (raw)

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Cell-Intrinsic Barriers of T Cell-Based Immunotherapy

Hazem E Ghoneim et al. Trends Mol Med. 2016 Dec.

Abstract

Prolonged exposure of CD8+ T cells to their cognate antigen can result in exhaustion of effector functions enabling the persistence of infected or transformed cells. Recent advances in strategies to rejuvenate host effector function using Immune Checkpoint Blockade have resulted in tremendous success towards the treatment of several cancers. However, it is unclear if T cell rejuvenation results in long-lived antitumor functions. Emerging evidence suggests that T cell exhaustion may also represent a significant impediment in sustaining long-lived antitumor activity by chimeric antigen receptor T cells. Here, we discuss current findings regarding transcriptional regulation during T cell exhaustion and address the hypothesis that epigenetics may be a potential barrier to achieving the maximum benefit of T cell-based immunotherapies.

Keywords: DNA methylation.; T cell exhaustion; chimeric antigen receptor T cells; epigenetics; histone modification; immune checkpoint blockade.

Copyright © 2016 Elsevier Ltd. All rights reserved.

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Figures

Key Figure, Figure 1

Key Figure, Figure 1. Epigenetic Barriers to Immune Checkpoint Blockade-Mediated Rejuvenation of T Cells

(A) The schematic depicts the repression in developmental plasticity acquired by antigen-specific T cells during clonal expansion in response to acute or chronic antigen exposure. Upon acute antigen exposure, naive CD8+ T cells clonally expand and differentiate into effector cells. During chronic high-level antigen exposure, persistent T cell receptor (TCR) stimulation can cause T cell exhaustion. Effector function is progressively repressed during the development of T cell exhaustion, thereby leading to a heterogeneous population of T cells at various levels of exhaustion. Partially exhausted T cells are phenotypically defined by sustained expression of a minimal number of immune inhibitory receptors (IRs) and characterized by differential expression of T-bet and Eomes (T-bethigh Eomeslow T cells), whereas fully exhausted T cells are marked by co-expression of multiple IRs. The immune checkpoint blockade (ICB) obstructs inhibitory signals from immune IRs, resulting in rejuvenation of partially exhausted T cells. (B) The schematic depicts the effect of progressive epigenetic programming that reinforces silencing of genes involved in effector function, proliferation, and metabolic fitness of exhausted T cells. Partially exhausted T cells may retain a degree of epigenetic plasticity at exhaustion-specific silenced genes manifested by partially methylated DNA and deposition of fewer repressive, more permissive histone marks. Terminally differentiated exhausted T cells may be more epigenetically restrained through fully methylated DNA, the deposition of more repressive histone marks, and the loss of permissive histone marks. (C) The diagram models the potential reprogramming of exhaustion-associated epigenetic programs that could be done to remove cell-intrinsic barriers to achieving a better, possibly durable rejuvenation response of fully exhausted T cells following ICB therapy.

Figure 2

Figure 2. Genetically-Engineered T cell Immunotherapeutic Approaches

The schematic depicts the multiuse process of generating genetically engineered human T cells targeted against specific tumor antigens. (Step 1) Autologous T cells can be isolated from a patient’s peripheral blood mononuclear cells or an excised tumor. (Step 2) T cell pools or specific subsets can be stimulated with (1) activating CD3 antibody (OKT3), (2) anti-CD3/CD28–coated beads, or (3) allogeneic feeder cell lines. (Step 3) Specific T cell subsets can be sorted or enriched according to their differentiation status to exploit proliferative and effector functions. (Step 4) Engineered T cells can be generated by cloning either T cell receptors (TCRs) or chimeric antigen receptors (CARs) and transducing a patient’s T cells with retro- or lenti-viruses, thus redirecting recognition toward tumor-associated antigens. (Step 5) Engineered T cells can then be expanded in vitro in the presence of conditioning cytokines (e.g., IL-2 or IL-15) to increase the frequency of tumor-specific T cells generated. (Step 6) Engineered T cells specific for an antigen (target) of interest are selected. (Step 7) Engineered T cells can then be reinfused into the patient (usually post-lymphodepletion).

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