Papa Toure

Combination of Tumor Site–Located CTL-Associated Antigen-4 Blockade and Systemic Regulatory T-Cell Depletion Induces Tumor-Destructive Immune Responses

Accumulating data indicate that tumor-infiltrating regulatory T cells (Treg) are present in human tumors and locally suppress antitumor immune cells. In this study, we found an increased Treg/CD8 ratio in human breast and cervical cancers. A similar intratumoral lymphocyte pattern was observed in a mouse model for cervical cancer (TC-1 cells). In this model, systemic Treg depletion was inefficient in controlling tumor growth. Furthermore, systemic CTL-associated antigen-4 (CTLA-4) blockade, an approach that can induce tumor immunity in other tumor models, did not result in TC-1 tumor regression but led to spontaneous development of autoimmune hepatitis. We hypothesized that continuous expression of an anti-CTLA-4 antibody localized to the tumor site could overcome Treg-mediated immunosuppression and locally activate tumor-reactive CD8+ cells, without induction of autoimmunity. To test this hypothesis, we created TC-1 cells that secrete a functional anti-CTLA-4 antibody (TC-1/alphaCTLA-4-gamma1 cells). When injected into immunocompetent mice, the growth of TC-1/alphaCTLA-4-gamma1 tumors was delayed compared with control TC-1 cells and accompanied by a reversion of the intratumoral Treg/CD8 ratio due to an increase in tumor-infiltrating IFNgamma-producing CD8+ cells. When local anti-CTLA-4 antibody production was combined with Treg inhibition, permanent TC-1 tumor regression and immunity was induced. Importantly, no signs of autoimmunity were detected in mice that received local CTLA-4 blockade alone or in combination with Treg depletion.

Promoter Hypermethylation of Tumor Suppressor Genes in Urine from Patients with Cervical Neoplasia

We examined the feasibility of using detection of high-risk human papillomavirus (HPV) DNA in combination with the presence of aberrantly methylated genes (DAPK1, RARB, TWIST1, and CDH13) for urine-based cervical cancer screening. Urine samples from 129 Senegalese women, aged 35 years or older, 110 with (same day) biopsy-proven cervical neoplasia [cervical intraepithelial neoplasia grade 1 (CIN-1): n = 9; CIN-2–3/carcinoma in situ (CIS): n = 29; invasive cervical cancer (ICC): n = 72], and 19 without cervical neoplasia on biopsy were examined. Hypermethylation of at least one of the four genes identified 62% of ICC and 28% of CIN-2–3/CIS and was present in only 4% of CIN-1 or normal urines. High-risk HPV DNA was detected in urine in 70% of those with biopsy-proven ICC, 59% of those with CIN-2–3/CIS on biopsy, 44% of those with CIN-1 on biopsy, and only 11% of women negative for cervical neoplasia on biopsy. Urine-based detection of either high-risk HPV or hypermethylation of any of the four genes identified 84% of ICC, 64% of CIN-2–3/CIS, 44% of CIN-1, but only 19% of women negative for cervical neoplasia. The sensitivity for detection of CIN-2–3/CIS/ICC by high-risk HPV DNA or aberrant DNA methylation of four genes seems to be comparable to that of an exfoliated cervical cytology. This study shows the potential feasibility of using molecular markers detected in urine for cervical cancer screening. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1178–84)

HIV infection as a risk factor for cervical cancer and cervical intraepithelial neoplasia in Senegal.

Cervical cancer is the second leading cause of cancer mortality in women worldwide, and the leading cause in Africa. There is uncertainty in the role of HIV infection as a risk factor for invasive and preinvasive cervical lesions, particularly in African populations. In a case-control study in Dakar, Senegal, we studied 150 women with invasive cervical cancer (ICC), 92 with cervical intraepithelial neoplasia (CIN) 2 or 3, 70 with CIN 1, and 515 control women. We used logistic regression analysis to estimate associations between HIV-1 and HIV-2 infection and the risk of cervical neoplasia. We found large increases in the risk of ICC and CIN 2-3, but not of CIN 1, associated with the presence of either HIV-1 or HIV-2 infection (odds ratios of 6.5 and 10.4 for ICC and CIN 2-3). Our analysis thus shows increases in the risk of both advanced and early cervical pathology associated with HIV infection in an African population. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2442–6)

Influence of HIV-1 and/or HIV-2 infection and CD4 count on cervical HPV DNA detection in women from Senegal, West Africa

BACKGROUND HIV infection is associated with greater risk of precancerous lesions and cervical cancer in women. However, several factors remain unclarified regarding the association between HIV infection and HPV detection, especially among those with HIV type 2 versus type 1 infection and severely immunocompromised persons. OBJECTIVES To evaluate HPV overall and type-specific detection among HIV-infected and uninfected women in Senegal. STUDY DESIGN Detection of HPV DNA for 38 genotypes in cervical swabs using PCR-based methods was evaluated in HIV-positive (n=467) and HIV-negative (n=2139) women participating in studies in Senegal. Among HIV-1 and/or HIV-2 positive women, CD4 counts were assessed. Adjusted multivariable prevalence ratios (PR) were calculated. RESULTS The prevalence of any HPV DNA and multiple HPV types was greater among HIV-infected individuals (78.2% and 62.3%, respectively) compared with HIV-negative women (27.1% and 11.6%). This trend was also seen for HPV types 16 and 18 (13.1% and 10.9%) compared to HIV-negative women (2.2% and 1.7%). HIV-infected women with CD4 cell counts less than 200 cells/μl had a higher likelihood of any HPV detection (PRa 1.30; 95% CI 1.07-1.59), multiple HPV types (PRa 1.52; 95% CI 1.14-2.01), and HPV-16 (PRa 9.00; 95% CI 1.66-48.67), but not HPV-18 (PRa 1.20, 95% CI 0.45-3.24) compared to those with CD4 counts 500 cells/μl or above. CONCLUSION HIV-infected women, especially those most severely immunocompromised, are more likely to harbor HPV. Measures to prevent initial HPV infection and subsequent development of cervical cancer through focused screening efforts should be implemented in these high risk populations.