Dysregulated Expression of Both the Costimulatory CD28 and Inhibitory CTLA-4 Molecules in PB T Cells of Advanced Cervical Cancer Patients Suggests Systemic Immunosuppression Related to Disease Progression

Abstract

Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients’ T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients. Conclusions: Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression.

Positive staining of the immunoligand B7-H6 in abnormal/transformed keratinocytes consistently accompanies the progression of cervical cancer

“…Abbreviations: LSIL: low-grade squamous intraepithelial lesion; HSIL: high-grade squamous intraepithelial lesion; SCC: squamous cervical carcinoma; UCAC: uterine cervical adenocarcinoma. ****p < 0.0005, ***p = 0.001, *p < 0.05 microenvironment of cervical cancer, until now, there have been no reports examining B7-H6 expression in cervical intraepithelial lesions or cervical cancer [26][27][28]. The findings of our present study demonstrate for the first time that B7-H6 is not expressed in the abnormal epithelial cells of low-grade squamous intraepithelial lesions (LSIL); while, in contrast, when the stage of the lesion is more advanced, such as high-grade squamous intraepithelial lesion (HSIL) or both cancer types, squamous cervical carcinoma (SCC) or uterine cervical adenocarcinoma (UCAC), there is a positive correlation with the immunoreactive score (IRS) for immunohistochemical B7-H6 detection.…”

Improving the efficiency of image guided brachytherapy in cervical cancer

“…This is a relatively underexploited facility but with new insights into the tumor microenvironment [56, 57, 58], particularly immune and inflammatory characteristics, and new therapeutic avenues such as immune checkpoint inhibition (e.g. PD-1 [59, 60, 61] and CTLA-4 [62, 63]), there is the opportunity to explore rational new drug-radiation combinations in partnership with technically optimized brachytherapy. This is the focus of a research programme at our institution.…”

Problems of Cancer Treatment. Part I. Theory of Treatment Based on Known Mechanisms of Anticancer Immunological Responses

“…The tumour-infiltrating lymphocytes T (tumor infiltrating lymphocytes, TILs) can be expected to recognise neoplastic antigens since on their surface activation markers appear, e.g. cytotoxic lymphocytes T CD8 + manifest surface expression of HLA-DR and CD38, which represents an important stage in further development of the lesion [71]. Nevertheless, the cells do not function effectively as tumour-combatting cells.…”

“…Anti-neoplastic response becomes actively altered by cancer cells [34,70,71]. The alteration takes place through the mechanism of modification affecting the environment in which the cancer develops, through secretion of suppressory cytokines, which stimulate cells which inhibit inflammatory response and through an increased expression of ligands for receptors of suppression and apoptosis (PD-L1, PD-L2, Fas-L) on cytotoxic cells [53,58,139].…”