High prevalence of abnormal cervical smears in a hospital cohort of French women beyond the upper age limit screening program.

OBJECTIVE: To determine the prevalence of cytological abnormalities and high risk Human PapillomaVirus (hrHPV) in cervical smears from French women aged over 65 years who attended the referent Gynecology Clinic of the Besançon University Hospital. METHODS: Between 2002 and 2012, 796 French women aged 66-99 years were cotested for cytology and hrHPV by Hybrid Capture 2 (hc2). hc2-positive cases were subjected to real time PCR for specific HPV 16/18/45 genotyping. Women with normal Pap smears and positive for hrHPV were followed-up every 12 months. RESULTS: Cytological abnormalities were detected in more than 30% of women and cervical cancers (CC) in 2.9% of women. Benign lesions were more frequent in women aged 66-75 years while (pre)-malignant lesions were preferentially found in women over 76. The prevalence of hrHPV was 22.7%. HPV 16 was the most frequent (23.8%), followed by HPV 45 (7.7%) and HPV 18 (3.9%). The rate of hrHPV increased with the lesion severity and HPV 16 was identified in 50% of CC. Among the followed-up women, those who developed CIN3 were HPV16 positive at study entry. CONCLUSION: The study provides important estimates of the prevalence of cervical abnormalities and hrHPV positivity in a French hospital based-population over 65. Findings suggest to consider this high risk population in regards to cervical cancer.

Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment.

Sorafenib, a multi-targeted kinase inhibitor, is the current standard systemic treatment for advanced hepatocellular carcinoma. Sorafenib has anti-angiogenic and anti-proliferative properties and is also known to favor anti-tumor T cell responses by reducing the population of immunosuppressive cells such as Treg and MDSC. Anti-tumor immune responses, especially mediated by CD4+ T-cells, are critical for tumor cells eradication and therapies modulating those responses are appealing in a growing number of cancers. Here, we report and investigate the case of a patient diagnosed with an advanced HCC treated by sorafenib who experienced a complete histological response. We aimed to identify immunogenic peptides derived from tumor mutated proteins that stimulated CD4+ T cells responses thus favoring the exceptional recovery process of this patient. Tumor neoantigens were identified using whole exome sequencing of normal and tumor tissue and peptide MHC binding prediction algorithms. Among 442 tumor-specific somatic variants, 50 missense mutations and 20 neoepitopes predicted to bind MHC-II were identified. Candidate neoepitopes immunogenicity was assessed by IFN-γ ELISpot after culture of patient's PBMCs in presence of synthetic neopeptides. CD4+ memory T cell responses were detected against a mutated IL-1ßS230F peptide and two additional neoepitopes from HELZ2V241M and MLL2A4458V suggesting that efficient anti-tumor immune response occurred in this patient. These results showed that T cells can recognize neoantigens and may lead to the cancer elimination after immunomodulation in the tumor-microenvironment induced by sorafenib. This observation indicates that other immunotherapies in combination with sorafenib could potentially increase the response rate in HCC at advanced stage.

Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity.

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3 (+)Helios(+)Ki67(+) regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes(+)CD8(+) T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100-12. ©2016 AACR.