Loss of Heterozygosity (LOH) Affecting HLA Genes in Breast Cancer: Clinical Relevance and Therapeutic Opportunities

Abstract

Major histocompatibility complex (MHC) class-I molecules (or Human Leucocyte Antigen class-I) play a key role in adaptive immunity against cancer. They present specific tumor neoantigens to cytotoxic T cells and provoke an antitumor cytotoxic response. The total or partial loss of HLA molecules can inhibit the immune system's ability to detect and destroy cancer cells. Loss of heterozygosity (LOH) is a common irreversible genetic alteration that occurs in the great majority of human tumors, including breast cancer. LOH at chromosome 6, which involves HLA genes (LOH-HLA), leads to the loss of an HLA haplotype and is linked to cancer progression and a weak response to cancer immunotherapy. Therefore, the loss of genes or an entire chromosomal region which are critical for antigen presentation is of particular importance in the search for novel prognostic and clinical biomarkers in breast cancer. Here, we review the role of LOH-HLA in breast cancer, its contribution to an understanding of cancer immune escape and tumor progression, and discuss how it can be targeted in cancer therapy.

Keywords: HLA class-I; LOH HLA; breast cancer; cancer immune escape.

Figure 1

Genomic organization of HLA genes and expression of HLA-I molecules on the cell membrane.

Figure 2

Antigen processing and presentation.

Figure 3

Reversible and irreversible HLA-I alterations (A) and corresponding expression profiles on the cell membrane (B).

Figure 4

Schematic illustration of HLA-I haplotype loss associated with LOH-HLA.

Figure 5

Schematic illustration of the CAR-T cells (with blocker and activator domains) that are activated after recognition of the tumor antigen on a tumor cell that does not express one HLA allele (HLA-A2). Adapted from [78,79].