HLA Class I Antigen Processing Machinery Defects in Cancer Cells—Frequency, Functional Significance, and Clinical Relevance with Special Emphasis on Their Role in T Cell-Based Immunotherapy of Malignant Disease

Abstract

MHC class I antigen abnormalities have been shown to be one of the major immune escape mechanisms murine and human cancer cells utilize to avoid recognition and destruction by host immune system. This mechanism has clinical relevance, since it is associated with poor prognosis and/or reduced patients' survival in many types of malignant diseases. The recent impressive clinical responses to T cell-based immunotherapies triggered by checkpoint inhibitors have rekindled tumor immunologists and clinical oncologists' interest in the analysis of the human leukocyte antigen (HLA) class I antigen processing machinery (APM) expression and function in malignant cells. Abnormalities in the expression, regulation and/or function of components of this machinery have been associated with the development of resistances to T cell-based immunotherapies. In this review, following the description of the human leukocyte antigen (HLA) class I APM organization and function, the information related to the frequency of defects in HLA class I APM component expression in various types of cancer and the underlying molecular mechanisms is summarized. Then the impact of these defects on clinical response to T cell-based immunotherapies and strategies to revert this immune escape process are discussed.

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

“…Furthermore, an impaired function of one of the APM components can also reduce the expression of HLA class I derived peptide complex [ 145 ]. Lastly, down-regulation of HLA class I antigen complex can be caused by alterations in the transcription factors forming the enhanceosome which bind SXY module on HLA class I heavy chain promoters [ 148 , 169 , 170 , 171 , 172 ]. Specifically, the expression and function of the NLRC5/CITA trans-activator can be affected by promoter methylation, copy number loss and somatic mutations [ 173 , 174 ].…”

“…Their frequency ranges from 10-84% in the cases analyzed [ 100 , 180 , 181 , 182 , 183 , 184 ]. TAP abnormalities reduce the translocation of peptides into the ER, resulting in a decreased formation of stable HLA class I derived peptide complexes or expression of “peptide-free” HLA class I molecules [ 171 , 172 ]. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8+ T-cell immunity is sufficiently supported by an increased number of alternative TAP-independent processing pathways [ 171 , 172 ].…”

“…TAP abnormalities reduce the translocation of peptides into the ER, resulting in a decreased formation of stable HLA class I derived peptide complexes or expression of “peptide-free” HLA class I molecules [ 171 , 172 ]. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8+ T-cell immunity is sufficiently supported by an increased number of alternative TAP-independent processing pathways [ 171 , 172 ]. Identification of these alternative loading mechanisms into peptide-receptive HLA class I molecules still needs further investigation.…”

Identification of microRNAs Targeting the Transporter Associated with Antigen Processing TAP1 in Melanoma

“…Human solid tumors including melanoma develop different strategies to escape T cell-mediated immune surveillance such as loss or downregulation of human leukocyte antigens (HLA) class I molecules. This is frequently due to defects in the expression of various components of the antigen processing and presentation machinery (APM), which can be associated with disease progression and reduced patient survival [1][2][3][4]. Alterations in the HLA class I pathway may be a result of the selective pressure of the immune system and could occur in patients treated with immunotherapies [5,6].…”

“…During the last few decades, the underlying molecular mechanisms of HLA class I and APM component deficiencies have been characterized demonstrating a high diversity, ranging from deregulation to rather rare structural alterations [3,[7][8][9]. The deregulation of HLA class I APM components in tumors could occur at the transcriptional, epigenetic, posttranscriptional and/or posttranslational level and depend on the tumor type analyzed [2,[10][11][12]. Recently, the posttranscriptional regulation of HLA class I APM components has come into focus, which could be mediated by RNA binding proteins (RBP) or small non-coding microRNAs (miRs) [13][14][15][16].…”