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.

Keywords: HLA class I antigens; Immune checkpoint; Immunotherapy; NIBIT 2016; Targeted therapy.

Fig. 1

Frequency of HLA class I heavy chain and β2m expression defects by tumor type. The number of included studies (number of cases) for each tumor type is presented within each bar. Error bars represent the maximum and minimum expression defect frequency reported

Fig. 2

Frequency of defects in HLA class I APM immunoproteasome subunit expression by tumor type. The number of included studies (number of cases) for each tumor type is presented within each bar. Error bars represent the maximum and minimum expression defect frequency reported

Fig. 3

Frequency of defects in HLA class I APM transporter molecule expression by tumor type. The number of included studies (number of cases) for each tumor type is presented within each bar. Error bars represent the maximum and minimum expression defect frequency reported

Fig. 4

Frequency of defects in HLA class I APM chaperone expression by tumor type. The number of included studies (number of cases) for each tumor type is presented within each bar. Error bars represent the maximum and minimum expression defect frequency reported

Fig. 5

Higher frequency of HLA class I expression defects in formalin-fixed paraffin embedded (FFPE) tissue sections than in and frozen tissue sections, by tumor type. The number of included studies (number of cases) for each tumor type is presented within each bar. Error bars represent the maximum and minimum expression defect frequency reported

Fig. 6

Role of selective pressure in the generation of tumors with defective HLA class I APM component expression. a Abnormalities in HLA class I APM component expression and/or function do not appear to have an effect on the growth of tumor cells in an immunologically naïve environment. As a result, in the absence of selective pressure the representation of subpopulations with defective HLA class I APM expression and of those with no detectable defects is not likely to change in the course of the disease. b The selective pressure imposed by a host’s immune response facilitates the outgrowth of tumor cells which can escape recognition by cognate T cells because of defective presentation of tumor antigen-derived peptides caused by abnormality (ies) in HLA class I APM. As a result, tumor cells with defective HLA class I APM become the major population in a tumor

Fig. 7

Frequency of HLA class I APM component mutations. The tumor type(s) with the highest frequency of mutation for each component is indicated within each bar

Fig. 8

Events leading to lack of β2m (a) and APM component (b) expression. a β2m loss results from two cancer-related events: inactivation of one β2m encoding gene because of a mutation and LOH on chromosome #15 which carries the wild-type β2m gene. b APM component loss is caused by one germline mutation and one somatic cancer-related mutation, or by one LOH on chromosome #6 and one germline mutation in malignant cells (LOH: loss of heterozygosity)