ASSOCIATIONS BETWEEN POLYMORPHISMS AND ABNORMAL RPFNA CYTOMORPHOLOGY IN HIGH-RISK POSTMENOPAUSAL WOMEN TAKING HRT

Introduction: Hormone replacement therapy (HRT) is an effective treatment option for women experiencing symptoms of menopause but long-term use is associated with an increased risk of breast cancer. HRT-related breast cancer risk is dependent on many other factors including age at menopause, age at initiation of therapy, duration of use, dose and method of delivery. Differences in genetic factors, specifically single nucleotide polymorphisms (SNP) may identify those women whose breast tissue is likely or unlikely to be seriously affected by HRT. Methods: Post-menopausal women at increased risk for breast cancer underwent breast tissue sampling by random periareolar fine needle aspiration (RPFNA) and epithelial cells were characterized as to whether they exhibited cytologic evidence of hyperplasia with atypia. DNA was isolated from buccal cells for assessment of candidate genes involved in steroid metabolism, receptor function, cell cycle control, DNA repair and/or carcinogen metabolism. Associations between each SNP and RPFNA atypia were examined by unconditional logistic regression in three different genetic models: a log-additive, dominant, and co-dominant. Linear regression was used to assess the association between each SNP and worsening cytomorphology while taking systemic HRT for ≥ 6 months vs. off systemic HRT. The adjusted significance level, pResults: RAD54 Gln929Glu, TFR Gly142Ser, VEGF 3'UTR and ACE16 I/D were associated with RPFNA atypia in all women at pTFR Gly142Ser reached borderline significance (p=0.0025). Interestingly, the cohort of women with RPFNA cytomorphology both while taking HRT and off HRT showed the most significant results. RAD23B Ala249Val was significantly associated with worsening cytomorphology while on HRT vs. off HRT (p=0.0009) and ERCC1 3'UTR was borderline (p=0.0015). SNPs associated with worse cytomorphology showed similar effects when we defined the outcome variable as evidence of atypia while on systemic HRT with no atypia while off systemic HRT. Conclusion: Promising associations exist between polymorphisms involved in DNA repair and worse RPFNA cytomorphology as a consequence of HRT use. However, given the probability of chance finding due to multiple testing, these results will need to be validated in an independent cohort

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Nanostructured Surfaces and Assemblies as SERS Media

Metallic nanostructures attract much interest as an efficient media for surface-enhanced Raman scattering (SERS). Significant progress has been made on the synthesis of metal nanoparticles with various shapes, composition, and controlled plasmonic properties, all critical for an efficient SERS response. For practical applications, efficient strategies of assembling metal nanoparticles into organized nanostructures are paramount for the fabrication of reproducible, stable, and highly active SERS substrates. Recent progress in the synthesis of novel plasmonic nanoparticles, fabrication of highly ordered one-, two-, and three-dimensional SERS substrates, and some applications of corresponding SERS effects are discussed.close35233