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Review
. 2016 Jul:58:52-8.
doi: 10.1016/j.oraloncology.2016.05.008. Epub 2016 Jun 2.

Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells

Fernando Concha-Benavente  1 , Raghvendra Srivastava  2 , Soldano Ferrone  3 , Robert L Ferris  4
Affiliations
Review

Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells

Fernando Concha-Benavente et al. Oral Oncol. 2016 Jul.

Abstract

Experimental as well as clinical studies demonstrate that the immune system plays a major role in controlling generation and progression of tumors. The cancer immunoediting theory supports the notion that tumor cell immunogenicity is dynamically shaped by the immune system, as it eliminates immunogenic tumor cells in the early stage of the disease and then edits their antigenicity. The end result is the generation of a tumor cell population able to escape from immune recognition and elimination by tumor infiltrating lymphocytes. Two major mechanisms, which affect the target cells and the effector phase of the immune response, play a crucial role in the editing process. One is represented by the downregulation of tumor antigen (TA) processing and presentation because of abnormalities in the HLA class I antigen processing machinery (APM). The other one is represented by the anergy of effector immune infiltrates in the tumor microenvironment caused by aberrant inhibitory signals triggered by immune checkpoint receptor (ICR) ligands, such as programmed death ligand-1 (PD-L1). In this review, we will focus on tumor immune escape mechanisms caused by defects in HLA class I APM component expression and/or function in different types of cancer, with emphasis on head and neck cancer (HNC). We will also discuss the immunological implications and clinical relevance of these HLA class I APM abnormalities. Finally, we will describe strategies to counteract defective TA presentation with the expectation that they will enhance tumor recognition and elimination by tumor infiltrating effector T cells.

Keywords: APM; CTL; HLA class I; Immunoescape.

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Conflict of interest statement

statement The authors disclose no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Antigen processing machinery (APM) components. Normal cells process intracellular ubiquitinated proteins tagged for degradation via the proteasome generating peptide fragments that are loaded onto nascent HLA class I molecules inside the endoplasmic reticulum (ER). Antigen presentation on the cell surface requires intact APM machinery in order to stimulate specific CD8+ T cell effector responses.
Fig. 2
Fig. 2
The cancer genome atlas (TCGA) mutational landscape of APM components in head and neck cancer. (A) TCGA data from 279 HNC specimens with whole sequencing and copy number alterations (CNA) was accessed via the cBio portal (www.cbioportal.org). 20% of specimens (55/279) harbored genetic alterations in the APM gene sequences queried. An OncoPrint view was generated for each gene queried, the most altered APM genes were TAP2 (4%), TAP1 (3%), HLA-A and HLA-B (3% respectively) and PSMB7 (LMP7, 3%). Interestingly the mutations found in the HLA-A and HLA-B loci were almost exclusively truncating or missense mutations (black and green slots, respectively) while for the rest of the APM genes queried were mostly gene amplifications or deletions (red and blue slots, respectively). B2M, β2-microglobulin; TAPBP, tapasin; CANX, calnexin; CALR, calreticulin; PDIA3, ERP57; PSMB2, LMP2; PSMB7, LMP7; PSMB10, LMP10. (B) Disease free Kaplan–Meier survival curve of 276 HNC tumor specimens annotated in the TCGA with clinical data available showed that cancer patients with no genetic alterations in the APM components had better prognosis than those who had alterations (53.09 vs. 32.82 median months disease free). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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