Cell-Intrinsic Barriers of T Cell-Based Immunotherapy. Issue 12 (December 2016)

• Record Type: Journal Article
• Authors: Ghoneim, Hazem E.; Zamora, Anthony E.; Thomas, Paul G.; Youngblood, Ben A.
• Is Part Of: Trends in molecular medicine. Volume 22:Issue 12(2016)
• Page Start: 1000
• Page End: 1011
• Publication Date: 2016-12
• Subjects: immune checkpoint blockade -- chimeric antigen receptor T cells -- T cell exhaustion -- epigenetics -- histone modification -- DNA methylation.; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2016.10.002
• Languages: English
• ISSNs: 1471-4914

Abstract

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. Trends: Immune checkpoint blockade-mediated expansion of partially exhausted CD8 + T cell has resulted in unprecedented clinical responses in multiple types of cancer. Multiple hallmarks of transcriptional programming during the development of T cell exhaustion are stably inherited, even after the level of specific antigen has diminished. The stability of a permissive transcriptional program at the PD-1 promoter in exhausted CD8 + T cells is coupled to stable epigenetic modifications. Exhausted T cells remain partially refractory to immune checkpoint blockade therapy, even after resting in an antigen-free environment. Current CAR T cell therapeutic approaches remain vulnerable to T cell exhaustion.