CD74 and HLA-DRA in Cervical Carcinogenesis: Potential Targets for Antitumour Therapy

Abstract

Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins’ expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins’ expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects’ age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies.

The Micro-Immunotherapy Medicine 2LPAPI® Displays Immune-Modulatory Effects in a Model of Human Papillomavirus Type-16 L1-Protein Capsid-Treated Human Peripheral Blood Mononuclear Cells and Antiproliferative Effects in a Model of Cervical Cancer Cells

“…Moreover, in the context of genital warts and pre-cancerous cervical lesions, HLA-DR targeting could be an effective strategy, as its expression appears to be increased through the carcinogenic process of cervical cancer [75]. For instance, transcriptomics profiles and protein expressions were assessed in samples from normal cervixes, HPV types 16/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC), demonstrating upregulations of CD74 and HLA-DRA from normal cervix to CIN with the highest in SCC [76].…”

Reduced MHC Class I and II Expression in HPV−Negative vs. HPV−Positive Cervical Cancers

“…In comparison, the normalized read levels of MHC class II gene expression appeared comparable to that of epithelial ( CDH1 ) and macrophage ( CD68 , CD163 ) specific genes. Although mRNA expression does not directly translate to protein levels within the tumor, numerous studies using immunohistochemistry (IHC) to investigate MHC class II expression in CC have conclusively shown high expression of these heavy chain proteins and proteins involved in MHC class II antigen presentation by the carcinoma cells [ 84 , 85 , 86 , 87 , 88 ]. These findings support our interpretation that epithelial cells within the actual tumor are coordinately expressing high levels of MHC class II genes, and potentially serving as amateur APCs in this moderately inflamed TME [ 83 ].…”

MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy

“…Importantly, a recent analysis of cellto-cell interactions in the context of lung adenocarcinoma predicted the involvement of the MIF-CD74 signaling axis in intercellular communication between regulatory T cells and other cells in the tumor microenvironment, including fibroblasts, epithelial cells, and B cells [59]. While a comprehensive discussion of MIF and CD74 in cancer is outside the scope of this work, the interested reader is referred to several excellent reviews on this topic [21,32,51,55,60].…”

“…[12][13][14][15][16][17][18][19][20]. In addition, MIF and CD74 have been identified as potential targets of anti-cancer therapeutics, including for cervical cancer [21], ovarian carcinoma [15], glioblastoma [22], multiple myeloma [23][24][25][26], and melanoma [12,[27][28][29]. Pertinent to this area of study, multiple MIF modulators are currently being investigated as targets for anti-cancer treatment [30].…”