MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells

Abstract

The surface presentation of peptides by major histocompatibility complex (MHC) class I molecules is critical to all CD8(+) T-cell adaptive immune responses, including those against tumors. The generation of peptides and their loading on MHC class I molecules is a multistep process involving multiple molecular species that constitute the so-called antigen processing and presenting machinery (APM). The majority of class I peptides begin as proteasome degradation products of cytosolic proteins. Once transported into the endoplasmic reticulum by TAP (transporter associated with antigen processing), peptides are not bound randomly by class I molecules but are chosen by length and sequence, with peptidases editing the raw peptide pool. Aberrations in APM genes and proteins have frequently been observed in human tumors and found to correlate with relevant clinical variables, including tumor grade, tumor stage, disease recurrence, and survival. These findings support the idea that APM defects are immune escape mechanisms that disrupt the tumor cells' ability to be recognized and killed by tumor antigen-specific cytotoxic CD8(+) T cells. Detailed knowledge of APM is crucial for the optimization of T cell-based immunotherapy protocols.

Multiparametric immune profiling in HPV– oral squamous cell cancer

“…Thus, higher cytoplasmic expression of HC and β 2 m might indicate a defect in the export of MHC class I molecules to the cell surface, a mechanism already described in virus-infected cells, leading to reduced T cell-mediated killing (47). So far, altered MHC class I APM component expression in HNSCC and other cancers has been documented by others but has not been correlated to the immune cell infiltrate of the tumor specimen (48)(49)(50). The underlying molecular mechanisms of the disturbed APM component expression have not been analyzed in detail, but deregulation, rather than structural abnormalities, appears to be main cause (51).…”

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

“…11 In this cylindrical 26S proteolytic complex, some of the catalytic subunits can be exchanged in response to changing cellular environments. In particular, the b subunits D, z, and MB1 can be replaced by the bi subunits LMP2, LMP7, and LMP10, respectively.…”

The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

“…28 T cells can also be genetically modified with natural or engineered T cell receptors (TCRs), which recognize peptides presented in the context of major histocompatibility complex (MHC). By combining genetic analysis of mutations in cancer cells with immune-peptidome analysis by mass spectrometry, a wave of new peptide antigen targets that can be recognized by endogenous TCRs 29,30 has potential for therapeutic development. Furthermore, new molecular methods that allow for the analysis of post-translationally modified (PTM) proteins has further increased the repertoire of new candidates amenable for T cell recognition.…”