Signaling Defects and Functional Impairment in T-Cells from Cervical Cancer Patients

Abstract

The ability of T-lymphocytes to recognize antigens and transduce signals to the nucleus successfully is a key component in the initiation and maintenance of an immune response. The present study addressed the expression status of the signal-transducing proteins in relation to the immune impairment in cervical cancer patients. Immune response was measured by evaluating lymphocyte subpopulations CD3(+), CD4(+), and CD8(+), using flowcytometry, natural killer cell activity, using the single-cell cytotoxicity assay, lymphocyte function, using mitogenic response to PHA and T-cell activation following anti-CD3 stimulation, and production of IL-2. Expression of the T-cell signal transduction proteins, TCR-zeta, CD3-epsilon, zap-70, p(56)lck, PKC, NFkappabeta p50, Rel-A, Rel-B, and c-rel, was evaluated by using Western blot assay. A generalized depression of the immune response with respect to the different parameters evaluated was observed. Exogenous interleukin-2 (IL-2) could increase the response in all the controls and in 30% of the patients to different degrees varying from 10% to 90%. Low levels of the signaling molecules (TCR-zeta, CD3-epsilon, zap-70, p(56)lck, and PKC) and impairment in the transduction of NFkappabeta components (p50, Rel-A, Rel-B, and c-rel) to the nuclei were observed in these lymphocytes. Decreased CD4(+)/CD8(+) ratio with an increase in suppressor cells, reduced lymphocyte proliferation, and production of IL-2 suggest a defective immune regulation in cervical cancer. Impairment in the translocation of NFkappabeta p50, Rel-A, and Rel-B to the nucleus and the reduced levels of signal-transducing proteins might be responsible for the decreased production of IL-2 and immune impairment in cervical cancer patients.

The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next?

“…When BV-associated strict anaerobes are able to colonise, they produce enzymes and metabolites, which may compromise this barrier, facilitating HPV entry. They also act on several cellular pathways that can enable a persistent, productive viral infection and subsequent disease development and progression [68–72]. Indirect evidence generated by existing mechanistic studies in vivo and in vitro in complementary fields and models of BV, as well as studies of other viral genital infections, supports potential mechanisms that warrant further investigation.…”

Early Pregnancy Factor Enhances the Generation and Function of CD4⁺CD25⁺ Regulatory T Cells

“…It has been demonstrated that EPF can suppress the immune system by reducing T-cell proliferation and cytokine production (Rabinowich et al 1996;Reichert et al 1998;Cheriyan et al 2009). However, the contribution of EPF to Treg differentiation and function has not been previously described.…”

Location and Density of Immune Cells in Precursor Lesions and Cervical Cancer

“…Zehbe et al 2007 showed that CD8+ cells specific for the HPV 16 E6 protein fail to control tumor growth despite interferon gamma production [33] suggesting that successful immune surveillance of HPV16+ tumor cells in cervical cancer patients is impaired. There are observations that those cells may be rendered tolerant by molecules present in tumor microenviroment [34,35]. Cervical tumors are marked by the presence of an immune regulatory microenvironment characterized by increased production of IL10 and TGFβ and decreased production of IL2 [31].…”