T.B. Turner

Ovarian cancer and the immune system — The role of targeted therapies

The majority of patients with epithelial ovarian cancer are diagnosed with advanced disease. While many of these patients will respond initially to chemotherapy, the majority will relapse and die of their disease. Targeted therapies that block or activate specific intracellular signaling pathways have been disappointing. In the past 15years, the role of the immune system in ovarian cancer has been investigated. Patients with a more robust immune response, as documented by the presence of lymphocytes infiltrating within their tumor, have increased survival and better response to chemotherapy. In addition, a strong immunosuppressive environment often accompanies ovarian cancer. Recent research has identified potential therapies that leverage the immune system to identify and destroy tumor cells that previously evaded immunosurveillance mechanisms. In this review, we discuss the role of the immune system in ovarian cancer and focus on specific pathways and molecules that show a potential for targeted therapy. We also review the ongoing clinical trials using targeted immunotherapy in ovarian cancer. The role of targeted immunotherapy in patients with ovarian cancer represents a field of growing research and clinical importance.

Epigenetic modifiers upregulate MHC II and impede ovarian cancer tumor growth

Expression of MHC class II pathway proteins in ovarian cancer correlates with prolonged survival. Murine and human ovarian cancer cells were treated with epigenetic modulators – histone deacetylase inhibitors and a DNA methyltransferase inhibitor. mRNA and protein expression of the MHC II pathway were evaluated by qPCR and flow cytometry. Treatment with entinostat and azacytidine of ID8 cells in vitro increased mRNA levels of Cd74, Ciita, and H2-Aa, H2-Eb1. MHC II and CD74 protein expression were increased after treatment with either agent. A dose dependent response in mRNA and protein expression was seen with entinostat. Combination treatment showed higher MHC II protein expression than with single agent treatment. In patient derived xenografts, CIITA, CD74, and MHC II mRNA transcripts were significantly increased after combination treatment. Expression of MHC II on ovarian tumors in MISIIR-Tag mice was increased with both agents relative to control. Combination treatment significantly reduced ID8 tumor growth in immune-competent mice. Epigenetic treatment increases expression of MHC II on ovarian cancer cells and impedes tumor growth. This approach warrants further study in ovarian cancer patients.

The impact of physician burnout on clinical and academic productivity of gynecologic oncologists: A decision analysis

OBJECTIVE Physician burnout is associated with mental illness, alcohol abuse, and job dissatisfaction. Our objective was to estimate the impact of burnout on productivity of gynecologic oncologists during the first half of their career. METHODS A decision model evaluated the impact of burnout on total relative value (RVU) production during the first 15years of practice for gynecologic oncologists entering the workforce from 2011 to 2015. The SGO practice survey provided physician demographics and mean annual RVUs. Published data were used to estimate probability of burnout for male and female gynecologic oncologists, and the impact of depression, alcohol abuse, and early retirement. Academic productivity was defined as annual PubMed publications since finishing fellowship. RESULTS Without burnout, RVU production for the cohort of 250 gynecologic oncologists was 26.2 million (M) RVUs over 15years. With burnout, RVU production decreased by 1.6 M (5.9% decrease). Disproportionate rates of burnout among females resulted in 1.1 M lost RVUs for females vs. 488 K for males. Academic production without burnout was estimated at 9277 publications for the cohort. Burnout resulted in 1383 estimated fewer publications over 15years (14.9%). CONCLUSIONS The impact of burnout on clinical and academic productivity is substantial across all specialties. As health care systems struggle with human resource shortages, this study highlights the need for effective burnout prevention and wellness programs for gynecologic oncologists. Unless significant resources are designated to wellness programs, burnout will increasingly affect the care of our patients and the advancement of our field.

HPV vaccines: Translating immunogenicity into efficacy

ABSTRACT Currently available human papillomavirus (HPV) vaccines are very successful at preventing persistent HPV infection and premalignant cervical lesions. In part due to the unique aspects of HPV immunogenicity and high levels of efficacy no immune correlate has been identified for HPV vaccination. Serum neutralizing antibodies are used to measure vaccine response, but their role as a correlate has not been verified, and this theory fails to explain the prevention of HPV related non-mucosal lesions. Identifying a true correlate would aid in future work in this area but will be difficult in the setting of a highly efficacious vaccine.

Abstract 4030: Epigenetic induction of MHC-II pathway expression in murine ovarian cancer cell line

INTRODUCTION This study evaluated the potential of epigenetic treatments to induce the expression of the MHC-II antigen presentation pathway in ovarian cancer. Ovarian cancer escapes immune response allowing it to spread in the peritoneal cavity; however, patients with greater immune response to their tumors at baseline have improved survival. Typically, exogenous antigens from tumors are processed and presented via MHC-II to CD4 T cells by antigen-presenting cells. However, if ovarian cancer cells could be induced to express the MHC-II pathway, they could be converted into antigen presenting cells and stimulate an anti-tumor response. METHODS Murine epithelial ovarian cancer cells (ID8) were treated for 72 h with the histone deacetylase inhibitors (HDACi): entinostat (MS-275) (1.25, 2.5, 5, 10 μM) and quisinostat (20, 40, 80, 160 nM). Cells were treated with 5-azacytidine (5-aza), a DNA methytransferase inhibitor, alone and in combination with MS-275 (5 μM) at 17.25, 37.5, 75, and 150 nM. After treatment, the expression of CD74 (an MCH-II pathway protein) and MHC-II was evaluated by flow cytometry. Reverse transcription polymerase chain reaction (RT-PCR) analysis was performed to measure CD74 and CIITA, a transcriptional coactivator that controls MHC-II gene expression. RNA was extracted using RNEasy Mini Kit (Qiagen), cDNA was created with SuperScript VILO Master Mix (ThermoFischer), and a 109bp amplicon was created using JumpStart REDTaq ReadyMix (Sigma-Aldrich). For statistical analysis, a Welch ANOVA was performed using JMP Pro 12. Tukey-Kramer analysis evaluated individual differences. The mean fluorescence intensities (MFI) for the combination treatments were compared using an unequal variance F-test. RESULTS Increased protein expression of CD74 and MHC-II was seen after treatment with MS-275, quisinostat, and 5-aza compared to untreated control. Increased expression of CD74 and MHC-II was seen with the combination treatment of 5-aza (17, 37.5, 75, 150 nM) and MS-275 (5 μM) compared to individual treatments (p CONCLUSION Treatment with HDAC inhibitors and a DNA methyltransferase inhibitor induces expression of MHC-II in murine epithelial ovarian cancer cells. The conversion of ovarian cancer cells into antigen presenting cells provides a potential therapeutic model to augment the immune response against epithelial ovarian cancer, a disease known to suppress anti-tumor immunity. Citation Format: Taylor B. Turner, Rebecca C. Arend, Mei Li, Troy D. Randall, Andres Forero-Torres, Albert F. LoBuglio, J Michael Straughn, Donald J. Buchsbaum. Epigenetic induction of MHC-II pathway expression in murine ovarian cancer cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4030.