Human Immunology

Expression analysis of immune-regulatory molecules HLA-G, HLA-E and IDO in endometrial cancer

HLA-G has been widely implicated in advanced cancers through different pathways of immunosuppression allowing tumor escape. Contrarily, HLA-E has a controversial role in the tumor escape from the immune system. IDO catabolic enzyme is known to be up-regulated in many tumors types allowing their immune escape. Based on these considerations, we investigated the expression of HLA-G, HLA-E and IDO molecules in endometrial cancer (EC) and their association with prognostic clinicopathologic parameters. Their expression were checked in tumoral and adjacent endometrial tissues. Both HLA-G and IDO immunostaining were significantly increased in EC tissues compared to normal residual endometrial glands (Mann Whitney U-test, p = 0.0001 and p = 0,020 respectively). However, HLA-E was highly expressed in tumoral tissues as well as in normal residual endometrial glands (respectively, 100% and 81.8%). Increased HLA-G expression levels were observed in high histological grade (grade 3), and in the non-endometrioid type 2 EC. Unexpectedly, patients with IDO Low expression had significantly impaired overall survival compared to patients with IDO High (log-rank p = 0.021). Conversely, HLA-E low expression was associated to an improved overall survival EC (log-rank p = 0.004). We concluded that, HLA-G and IDO are highly expressed in EC compared to adjacent normal endometrial tissues, that might be interesting for the EC outcome.

Implication of IL-17 producing ɑβT and γδT cells in patients with ovarian cancer

To investigate the expression and cellular source of IL-17A in human ovarian cancer (OC), benign ovarian tumor (BOT) and borderline ovarian tumor (OBT). RT-PCR and immunohistochemistry were used to measure the expression level of IL-17A in human OC tissues. Find concrete source of the elevated IL-17A levels in OC tissues by flow cytometry. We found that IL-17A is expressed at higher levels in OC tissues than in BOT or OBT tissues at both the mRNA and protein levels. Moreover, high tumor IL-17A expression was significantly associated with poor tumor differentiation and positive lymph node status. Flow cytometric analysis demonstrated that significantly higher proportions of tumor-infiltrating IL-17A-producing CD4

Exploring the modulation of TLR4 and its associated ncRNAs in cancer immunopathogenesis, with an emphasis on the therapeutic implications and mechanisms underlying drug resistance

The clinical importance of IFN-γ and human epididymis protein 4 in Egyptian patients with epithelial ovarian cancer combined with HPV infection

High-grade Epithelial Ovarian Cancer (HGEOC) is an aggressive disease that usually presents at an advanced stage. Thus, detecting the circulating cytokines (IFNγ and TNF-α) may serve as a biomarker to identify malignancy and manage therapeutic decisions. Assessing the clinical importance of inflammatory mediators and tumor markers in EOC Egyptian patients compared with benign cases. Moreover, identifying the distinct inflammatory mediators in EOC patients combined with HPV infection. This study was conducted on 61 Egyptian patients, divided into 25 patients with HGEOC, 22 patients with LGEOC, and 14 benign ovarian tumor cases. Measurements of serum HE4, CA125, CEA, and CA19-9 were determined by Roche Elecsys immunoassays. Serum levels of TNF-α and IFN-γ were measured using quantitative sandwich ELISA. Quantitative genotyping of HPV DNA types 16, 18, and 45 was assessed for the HPV DNA-positive samples. HPV DNA was detected in 25.53 % of malignant cases, HPV 16 was detected in 50 % of HPV-positive cases, and only 1 case of HPV 18 was detected out of 12 positive cases. The Human Epididymis protein 4 (HE4) was statistically different between patients with EOC and benign cases (p-value = 0.007) and between HPV DNA positive and HPV DNA negative cases (p-value = 0.008). The serum levels of IFN- γ were statistically different between HGEOC and LGEOC (p-value < 0.001), while the serum levels of TNF-α didn't differ statistically between the two groups. IFN-γ could be used as a biomarker to discriminate HGEOC and LGEOC. Initial evidence for the possible association between HE4 and the progression of HPV-associated EOC was speculated.

The causal relationship between ankylosing spondylitis and the risk of ovarian cancer

The aim of this study was to investigate the potential causal relationship between ankylosing spondylitis (AS) and ovarian cancer. We conducted analyses utilizing publicly available pooled statistical data sets from genomewide association studies (GWAS) involving individuals of European ancestry. Our objective was to identify single nucleotide polymorphisms (SNPs) significantly associated with AS and use them as instrumental variables to assess the causal relationship between AS and ovarian cancer. We employed three statistical methods for two-sample Mendelian randomization: inverse variance weighting (IVW), weighted median, and MR-Egger regression. Network MR Analysis revealed the mediating role of tumor necrosis factor receptor superfamily member 21 between ankylosing spondylitis and ovarian cancer. From the GWAS on AS, we selected 23 instrumental SNPs that exhibited genome-wide significance. Our findings consistently demonstrated an association between AS and ovarian cancer using multiple statistical methods (IVW: odds ratio (OR) 1.147, 95% confidence interval (CI) 1.022-1.287; weighted median estimator: OR 1.177, 95% CI 1.009-1.373; MR-Egger regression: OR 1.166, 95% CI 0.958-1.418). These results indicate a positive correlation, suggesting that AS is associated with an increased risk of ovarian cancer. Furthermore, there was no evidence to suggest that the observed causal effect between AS and the risk of osteoarthritis was influenced by genetic pleiotropy (MR-Egger intercept = -0.0010644, P = 0.8433359). In addition, tumor necrosis factor receptor superfamily member 21 mediated 10.2% of the total effect size in the development of ankylosing spondylitis on ovarian cancer risk. Our Mendelian randomization analysis provides strong evidence supporting a potential causal relationship between AS and ovarian cancer risk, with ankylosing spondylitis clearly associated with an increased risk of ovarian cancer. Tumor necrosis factor receptor superfamily member 21 as a mediator involved in the occurrence and development of these two diseases.

Genetic polymorphisms of proteasome subunit genes of the MHC-I antigen-presenting system are associated with cervical cancer in a Chinese Han population

Proteasome subunit beta types 8 and 9 (PSMB8, PSMB9) play critical roles in the human leukocyte antigen class I (HLA I)-presenting system. Studies have suggested that polymorphisms in the PSMB8 and PSMB9 genes may influence the immune functions of PSMB8 and PSMB9, and thus be associated with various human cancers. We investigated associations involving single nucleotide polymorphisms (SNPs) rs2071543 in PSMB8, rs1351383, rs17587 and rs2127675 in PSMB9 and risk of cervical intraepithelial neoplasia (CIN) and cervical cancer in a Chinese Han population. A total of 543 patients with CIN, 1008 patients with cervical cancer, and 1120 healthy individuals were enrolled. Agena MassArray was used for SNP genotyping of PSMB8 and PSMB9. Associations involving these SNPs and risk of CIN and cervical cancer were analysed. Our results showed that the PSMB8 T/T and T/G genotypes of rs2071543 may be associated with a higher risk of CIN (P = 0.011, OR = 1.35,95% CI: 1.07-1.70) and cervical cancer (P = 0.006, OR = 1.31, 95% CI: 1.08-1.59). For rs17587, the A allele (P = 0.001, OR = 1.303, 95% CI: 1.115-1.522), and the A/A and A/G genotypes (P = 0.001, OR = 1.36, 95% CI: 1.13-1.63) may be risk factors for cervical cancer. These results indicated that PSMB8 rs2071543 might influence susceptibility to CIN and cervical cancer, and PSMB9 rs17587 might influence cervical cancer susceptibility in a Chinese Han population.

Function of gamma delta (γδ) T cell in cancer with special emphasis on cervical cancer

Cervical cancer is the second-most prevalent gynecologic cancer in India. It is typically detected in women between the ages of 35 and 44. Cervical cancer is mainly associated with the human papillomavirus (HPV). The report shows that 70 % of cervical cancer is caused by HPV 16 and 18. There are few therapeutic options and vaccines available for cervical cancer treatment and γδ T cell therapy is one of them. This therapy can kill various types of cancers, including cervical cancer. The major γδ T cell subset is the Vγ9Vδ2 T cell, mainly distributed in peripheral blood which recognize non-MHC peptide antigens and can eliminate MHC-downregulated cancer. Moreover, γδ T cells can express different types of receptors that bind to the molecules of stressed cells, often produced on cancerous cells but absent from healthy tissue. γδ T cells possess both direct and indirect cytotoxic capabilities against malignancies and show potential antitumoral responses. However, γδ T cells also encourage the progression of cancer. Cancer immunotherapy using γδ T cells will be a potential cancer treatment, as well as cervical cancer. This review focused on the γδ T cell and its function in cancer, with special emphasis on cervical cancer. It also focused on the ligand recognition site of γδ T cells, galectin-mediated therapy and pamidronate-treated therapy for cervical cancer. Instead of the great potential of γδ T cell for the eradication of cervical cancer, no comprehensive in-depth review is available to date, so there is a need to jot down the various roles and modes of action and different applications of γδ T cells for cancer research, which we believe will be a handy tool for the researchers and the readers.

MICA and KLRK1 genes and their impact in cervical intraepithelial neoplasia development in the southern Brazilian population

Cervical carcinoma and cervical intraepithelial neoplasia (CIN) are associated with persistent infection by oncogenic subtypes of HPV (Human Papillomavirus). Factors linked to immunity, genetics and others like oral contraceptive use, sexual behavior, coinfections with other microorganisms and smoking seem to influence the mechanisms that determine regression or progression to CIN and cervical cancer. We investigated the effect of the MHC class I chain-related gene A (MICA) and Killer Cell Lectin Like receptor K1 (KLRK1) genes on cervical cancer and CIN lesions susceptibility in a group of 195 patients from southern Brazil. There were found a significantly higher number of ex-smokers in the control group (p = 0.005). There were more oral contraceptives (OC) users in the patient group. MICA*008:01/04 allele showed a significant difference between patient and control groups (p = 0.03; OR = 0.63, 95% CI 0.41-0.96), as well as MICA*018:01(p = 0.004, OR = 0.15, 95% CI 0.03-0.64) and MICA*002:01/020 (p = 0.01; OR = 0.60, 95% CI 0.40-0.88). We also analyzed cases and controls according to the MICA-129 genotypes (Met/Val). There was found a difference (p = 0.02) with the Met/Val genotype in a higher frequency in controls and Val/Val and Val/MICA del at a higher frequency in the patient group. For the KLRK1 gene there was no significant difference between groups.

Prognostic implication of CD47 and CTLA-4 expressions in endometrial carcinoma

CD47 is an immune-regulatory protein that belongs to the immunoglobulin family. It inhibits the phagocytic ability of immune cells. So, it is related to an unfavorable outcome in leukemia and various solid tumors. One of the immune checkpoint molecules is cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) which interferes with anticancer immunity and has an important role in anti-cancer surveillance. This study aimed to investigate CD47 and CTLA-4 mRNA and protein expressions in relation to P53 mutation and different clinicopathological parameters in endometrial carcinoma (EC). We also investigated the relation between CD47 and CTLA-4 expressions in EC. This study included sixty-eight patients with EC. Tissue samples of the tumor with adequate safety margin were obtained. Part of the tissues was preserved in formalin for histopathological and immunohistochemical examination while the other part was kept frozen at -80 °C for molecular profile. CD47 and CTLA-4 gene expressions were upregulated in the tissues of EC in comparison with the adjacent control tissues. Significantly higher CD47 and CTLA-4 gene expressions were detected in the serous type, higher stage, muscle invasion ≥50 %, higher grade, LN metastasis, and distant metastasis. CD47 gene expression was a good marker of P53 mutation at a cut-off of 1.65. It showed a high sensitivity of 84 %, a high specificity of 75.3 %, an average PPV of 65.6 %, a high NPV of 88.9 %, and an accuracy of 77.9 % (P < 0.001). Similarly, CTLA-4 gene expression was a good marker of P53 mutation at a cut-off of 3.75. It showed a sensitivity of 88 %, a specificity of 74.3 %, a PPV of 66.7 %, an NPV of 91.4 %, and an accuracy of 79.4 % (P < 0.001). CD47 and CTLA-4 expressions can be considered possible diagnostic and prognostic markers in EC. They were good markers of P53 mutation, and higher tumor grades and stages.