Defective HLA class I antigen processing machinery in cancer

Abstract

Malignant transformation of cells is frequently associated with defective HLA class I antigen processing machinery (APM) component expression. This abnormality may have functional relevance, since it may have a negative impact on tumor cell recognition by cognate T cells. Furthermore, HLA class I APM abnormalities appear to have clinical significance, since they are associated with poor prognosis in several malignant diseases and may play a role in the resistance to immune checkpoint inhibitor-based immunotherapy. In this paper, we have reviewed the literature describing abnormalities in HLA class I APM component expression in many types of cancer. These abnormalities have been reported in all types of cancer analyzed with a frequency ranging between a minimum of 35.8% in renal cancer and a maximum of 87.9% in thyroid cancer for HLA class I heavy chains. In addition, we have described the molecular mechanisms underlying defects in HLA class I APM component expression and function by malignant cells. Lastly, we have discussed the clinical significance of HLA class I APM component abnormalities in malignant tumors.

NK Cell Infiltrates and HLA Class I Expression in Primary HER2+ Breast Cancer Predict and Uncouple Pathological Response and Disease-free Survival

“…For HLA-I staining by IHC, the use of HC10 mAb, provided a general yet partial view biased toward HLA-B and HLA-C expression assessment, including b2 microglobulin-free HLA-I heavy chains (37). Despite the fact that further studies addressing the molecular mechanisms underlying the specific HLA class I alterations in distinct tumors (21,22,38) would be of interest, the analysis implemented here might facilitate a meaningful stratification of patients with distinct clinical behaviors for treatment adaptation. The predictive value of both biomarkers deserve validation for their potential clinical utility in HER2-positive breast cancer, likely extending to general biomarkers for patients' stratification and selection for immunotherapy.…”

“…Expression of HLA class I molecules is an additional parameter determining the susceptibility of cancer cells to NK and CD8 T-cell recognition. Indeed, tumor-antigen (neoantigen) presentation by HLA class I is required for triggering tumor-specific CD8 T-cell cytotoxicity, a pathway commonly hijacked in different tumor types, including breast cancer (21)(22)(23). HLA-I downregulation facilitates NK-cell-mediated tumor cell recognition, whereas high HLA-I expression may repress NK-cell activation against tumors through interaction with inhibitory receptors of the KIR, CD94/ NKG2, and LILRB1 families (10)(11)(12).…”

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation

“…Tumor cells often acquire defects in the MHC-I antigen processing machinery [67]. Therefore, epitope cassette variants which facilitate epitope presentation may prove beneficial in oncolytic vaccination settings.…”

Role of Human Leukocyte Antigen System as A Predictive Biomarker for Checkpoint-Based Immunotherapy in Cancer Patients

“…Depending on tumor types, these defects have been associated with aggressive histopathological features as well as poor survival [ 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 ]. Most of the defects are caused by genetic or epigenetic mutations as well as by transcriptional or post-translational modifications [ 145 , 148 , 149 ]. These types of alterations can induce a total loss or down-regulation of HLA class I derived peptide complex as well as selective loss of HLA class I haplotypes or alleles ( Figure 1 ) [ 150 , 151 , 152 ].…”