Overexpressed Pseudogene HLA-DPB2 Promotes Tumor Immune Infiltrates by Regulating HLA-DPB1 and Indicates a Better Prognosis in Breast Cancer

Abstract

Immune checkpoint inhibitors (ICIs) have been successfully used for treating melanoma and non-small cell lung cancer. However, many patients with breast cancer (BC) show low response to ICIs due to the paucity of infiltrating immune cells. Pseudogenes, as a particular kind of long-chain noncoding RNA, play vital roles in tumorigenesis, but their potential roles in tumor immunology remain unclear. In this study that used data from online databases, the novel pseudogene <i>HLA-DPB2</i> and its parental gene <i>HLA-DPB1</i> were overexpressed and correlated with better prognosis in BC. Mechanistically, our results revealed that <i>HLA-DPB2</i> might serve as an endogenous RNA to increase <i>HLA-DPB1</i> expression by competitively binding with <i>has-miR-370-3p</i>. Functionally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the <i>HLA-DPB2/HLA-DPB1</i> axis was strongly relevant to immune-related biological functions. Further analysis demonstrated that high expression levels of the <i>HLA-DPB2</i> and <i>HLA-DPB1</i> were significantly associated with high immune infiltration abundance of CD8+ T cells, CD4+ T cells, Tfh, Th1, and NK cells and with high expression of majority biomarkers of monocytes, NK cell, T cell, CD8+ T cell, and Th1 in BC and its subtype, indicating that <i>HLA-DPB2</i> can increase the abundance of tumor-infiltrating lymphocytes in the BC microenvironment. Also, the <i>HLA-DPB2</i> and <i>HLA-DPB1</i> expression levels positively correlated with the expression levels of programmed cell death protein 1, programmed cell death ligand 1, and cytotoxic T-lymphocyte-associated antigen-4. Our findings suggest that pseudogene <i>HLA-DPB2</i> can upregulate <i>HLA-DPB1</i> through sponging has-miR-370-3p, thus exerting its antitumor effect by recruiting tumor-infiltrating immune cells into the breast tumor microenvironment, and that targeting the <i>HLA-DPB2/HLA-DPB1</i> axis with ICIs may optimize the current immunotherapy for BC.