Regulatory (FOXP3⁺) T cells as target for immune therapy of cervical intraepithelial neoplasia and cervical cancer

Abstract

Regulatory (FOXP3 + ) T cells (T regs ) comprise a subpopulation of CD4I ntense research has shown that regulatory T cells (T regs ) play a fundamental role in providing peripheral tolerance against auto and foreign antigens, whereas impairment of T reg function seems to be associated with different autoimmune diseases like systemic lupus erythematodes,(1) type 1 diabetes, (2) rheumatoid arthritis (3,4) and multiple sclerosis.(5) Particularly stimulating for oncologic research was that increased frequencies of T regs with suppressive activity were found in malignant tumors and in the blood of cancer patients.(6-9) Blocking of T reg function in murine tumor models resulted in strong cellular antitumor immunity and even complete tumor destruction, (10)(11)(12)(13)(14)(15) indicating a crucial role for T regs in tumor immunity.T regs represent a subpopulation of CD4 + T cells and account for approximately 10-15% of all CD4 + T cells. The most specific marker for T regs currently available is the transcription regulator FOXP3. + T regs an evolutionary conserved region within the foxp3 locus upstream of exon-1 displays complete DNA demethylation, known as the T reg -specific demethylated region (TSDR), whereas T cells with transient FOXP3 expression and thus non-permanent suppressive function, such as transforming growth factor-β induced T regs and recently activated conventional human T cells show a fully methylated TSDR. (18)(19)(20)(21) Little is known about factors that mediate homing of T regs in different organs or tumor tissue, but experimental data suggest that an interaction between organ-specific factors and T regs is required for their expansion and homing. (22)(23)(24) A highly selective switch for specific inactivation of murine T regs was identified by Shimon Sakaguchi and his colleagues.(25) He developed an agonistic antibody that binds to murine glucocorticoidinduced tumor necrosis factor receptor family-related protein (GITR). Activation of GITR in concert with antigen-specific stimulation of T regs abrogates their suppressive activity. Applying the anti-GITR antibody to BALB/c mice 8 days after inoculation of 2 × 10 5 Meth-A fibrosarcoma cells induced a strong antitumor immune response followed by complete tumor eradication in all treated animals.(25) One concern regarding possible side-effects of GITR activation was the unintended induction of autoimmune reactions, but organ function in mice remained unaltered during therapy and no autoimmune reactions were detected. (25) Despite their viral origin and well-defined target genes, clinical trials for immune therapy of cervical intraepithelial neoplasia (CIN) lesions and cervical cancer have been mostly ineffective. (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) Potentially acting as a tumor-protective shield, T reg may constitute an important reason for these failures, as their accumulation at the tumor site might render intended immunostimulation ineffective.In order to elucidate the prevalence of FOXP3 + T cells in CIN lesions, cervical cancer, colon can...

Glucocorticoid-induced tumor necrosis factor receptor expression in patients with cervical human papillomavirus infection

“…Given the fi ndings that indicate the involvement of cells with regulatory properties, especially T reg cells, in the progression of cervical malignant lesions 3,4,23,24 , this study aimed to detect both CD25 and GITR markers in lymphocytes of cervical stroma to better understand the immune response in the microenvironment of HPV infection, which may shed light on novel therapeutic interventions against intraepithelial neoplasia and cervical cancer of viral etiology, and perhaps also make GITR a possible candidate biomarker for disease evolution.…”

“…Studies have demonstrated increased frequencies and suppressive activity of T reg cells in patients with high-grade lesions and cervical cancer. In addition, compared to colorectal cancer, skin melanoma, and bronchial carcinoma, HPV-derived CIN lesions and cervical carcinomas have higher numbers of T reg cells 23,24 .…”

Eradication of large tumors expressing human papillomavirus E7 protein by therapeutic vaccination with E7 fused to the extra domain a from fibronectin

“…Indeed, a strong immune response might be inefficient and succumb to an overwhelming tumor. The recruitment of T regulatory cells found in humans in many types of tumors ( [33][34][35][36] and in particular in cervical carcinoma 37 ) is an important obstacle for cancer vaccines. In a previous work, we have found that tumor infiltrating Treg numbers increased over time in TC-1 tumors, reaching almost 50% of total CD4 þ cells 25 days after tumor inoculation.…”

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

“…Similarly, Piersma et al 31 found a significantly stronger CD8 1 T-cell tumor infiltration, a higher CD8 1 /CD4 1 T-cell ratio, and a higher CD8 1 /Tregs ratio in patients with tumors that failed to metastasize to the tumor-draining lymph node. Loddenkemper et al, 27 in a comparison study of high-grade CIN (CIN III) and cervical carcinoma with colon cancer, skin melanoma and bronchial carcinoma, revealed that HPV-derived lesions have a significantly higher number of infiltrating lymphocytes and FOXP3 1 Tregs as compared with three other common tumor types. Similar to the above studies, in our study, we observed a reversed CD4/CD8 ratio in cervical cancer.…”

“…25 Using an assay to determine the immune microenvironment of cervical cancer, others have shown a type II predominance. 26,27 Cervical cancer is one of the most common malignancies of married women globally and is the result of an uncontrolled persistent infection with a high-risk human papillomavirus (HPV) type, HPV16 and HPV18 in particular, which account for approximately two-thirds of these cancers. 28,29 The immune microenvironment of cervical cancer not only shares the nature of solid tumors in general, but also possesses the properties associated with its etiology.…”