96 research outputs found
Implications of Antigen Selection on T Cell-Based Immunotherapy
No full textMany immunotherapies rely on CD8+ effector T cells to recognize and kill cognate tumor cells. These T cell-based immunotherapies include adoptive cell therapy, such as CAR T cells or transgenic TCR T cells, and anti-cancer vaccines which expand endogenous T cell populations. Tumor mutation burden and the choice of antigen are among the most important aspects of T cell-based immunotherapies. Here, we highlight various classes of cancer antigens, including self, neojunction-derived, human endogenous retrovirus (HERV)-derived, and somatic nucleotide variant (SNV)-derived antigens, and consider their utility in T cell-based immunotherapies. We further discuss the respective anti-tumor/anti-self-properties that influence both the degree of immunotolerance and potential off-target effects associated with each antigen class
MHC Class I and MHC Class II Bind to Specific TCRs
No full text<p>MHC class I and MHC class II bind to specific TCRs on the surface of the MHC molecule that is facing you. The peptide is presented by the MHC to the TCR like a hotdog in a bun; the peptide typically constitutes approximately 15% and the MHC molecule constitutes approximately 85% of the surface that the TCR binds. (A) shows a molecular structure of the human MHC class I, HLA-A2, bound to a tumor antigen, MAGE-4 (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0000078#pbio.0000078-Hillig1" target="_blank">Hillig et al. 2001</a>). This structure is distinct from (B), which shows the human MHC class II molecule HLA-DR1 bound to a peptide derived from the Epstein–Barr virus gp42 protein (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0000078#pbio.0000078-Mullen" target="_blank">Mullen et al. 2002</a>) in three ways. (1) The MHC class I peptide is shorter (average of nine amino acids versus 15 amino acids). (2) The ends of the peptide-binding grooves are closed in the MHC class I. (3) Although it is not evident in the structures shown, the binding groove from MHC class II is produced from two distinct molecules; the groove from MHC class I forms from one protein. The class I and II molecules can be found in animals from jawed vertebrates on up the evolutionary tree. (Figure produced with Cn3D version 4 from the National Center for Biotechnology Information.)</p
Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity
No full textTranscription is a dynamic process influenced by the cellular environment: healthy, transformed, and otherwise. Genome-wide mRNA expression profiles reflect the collective impact of pathways modulating cell function under different conditions. In this review we focus on the transcriptional pathways that control tumor infiltrating CD8+ T cell (TIL) function. Simultaneous restraint of overlapping inhibitory pathways may confer TIL resistance to multiple mechanisms of suppression traditionally referred to as exhaustion, tolerance, or anergy. Although decades of work have laid a solid foundation of altered transcriptional networks underlying various subsets of hypofunctional or “dysfunctional” CD8+ T cells, an understanding of the relevance in TIL has just begun. With recent technological advances, it is now feasible to further elucidate and utilize these pathways in immunotherapy platforms that seek to increase TIL function
Granzymes: The Molecular Executors of Immune-Mediated Cytotoxicity
No full textCytotoxic T lymphocytes, differentiated CD8+ T cells, use multiple mechanisms to mediate their function, including release of granules containing perforin and granzymes at target cells. Granzymes are a family of cytotoxic proteases that each act on unique sets of biological substrates within target cells, usually to induce cell death. Granzymes are differentially expressed within T cells, depending on their environment and activation state, making the granzyme cytotoxic pathway dynamic and responsive to individual circumstances. In this review, we describe what is currently known about granzyme structure, processing, and granzyme-induced cell death in the context of cancer and in some other inflammatory diseases
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