HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

Abstract

The human leukocyte antigen (HLA) class II antigen-processing machinery (APM) presents to cognate CD4⁺ T-cells antigenic peptides mainly generated from exogeneous proteins in the endocytic compartment. These CD4⁺ T cells exert helper function, but may also act as effector cells, thereby recognizing HLA class II antigen-expressing tumor cells. Thus, HLA class II antigen expression by tumor cells influences the tumor antigen (TA)-specific immune responses and, depending on the cancer type, the clinical course of the disease. Many types of human cancers express HLA class II antigens, although with marked differences in their frequency. Some types of cancer lack HLA class II antigen expression, which could be due to structural defects or deregulation affecting different components of the complex HLA class II APM and/or from lack of cytokine(s) in the tumor microenvironment. In this review, we have summarized the information about HLA class II antigen distribution in normal tissues, the structural organization of the HLA class II APM, their expression and regulation in malignant cells, the defects, which have been identified in malignant cells, and their functional and clinical relevance.

Keywords: Antigen-processing; HLA class II; immune response, tumor.

Figure 1.

HLA class II antigen-processing and presentation pathway. In APCs, newly synthesized HLA class II molecules are assembled in the ER and bind the Ii. The Ii direct the transport of HLA class II molecules directly or indirectly into the MIIC, where the li is degraded by different proteases leaving the peptide fragment CLIP still embedded in the HLA class II binding groove. An HLA class II-like molecule, HLA-DM, facilitates the release of CLIP and assists in the exchange of CLIP with relevant exogeneous antigenic fragments. Then the HLA class II peptide complex is transported to cell surface for presentation to CD4⁺ T cells.