Epithelial ovarian cancer (OC) is the deadliest cancer of the female reproductive tract; an estimated 13,270 women will die from OC in 2023 (ACS 2023). The 5-year relative survival rate is 50.8%, primarily due to 1) the high percentage of women who are initially diagnosed with advanced stage disease and 2) the high rate of disease recurrence (SEER 2023). The standard treatment for OC participants includes surgical removal of the tumor(s) followed by first-line chemotherapy (combination therapy of platinum- and taxane- based drugs, carboplatin and paclitaxel) (Ledermann 2018). An estimated 85% of OC participants who reach full remission after first-line treatment will have disease recurrence (OCRA 2023). Participants are classified into three categories: platinum-sensitive, platinum-resistant or platinum-refractory, based on disease response to first-line chemotherapy and disease-free interval (Stuart et al. 2011). Investigations into potential biomarkers and mechanisms of chemo-responsiveness are extensive and include microRNAs, proteomics and cancer stem cells (Ye, 2015, Yu et al., 2017, van Zyl et al. 2018, Zhao et al. 2018). However, chemotherapy responsiveness and resistance mechanisms remain difficult to elucidate and contribute to the high mortality rate of OC.

Peripheral inflammation is linked to the development of various malignancies. T lymphocytes mediate an immune response through the secretion of cytokines which are associated with promoting an inflammatory or tolerant immune response within resident tissues. For this investigation, we focused on two specific T lymphocyte types: Th17 cells, a specific type of T helper cell, which are pro-inflammatory cells, whereas Tregulatory cells (Tregs) are a type of tolerant T cell that inhibit effector T cell activation. Peripheral T lymphocyte populations may vary among cancer patients, but the ratio of these populations may define a unique immune profile as either inflammatory or tolerant. Moreover, the interleukins IL-17, IL-21 and IL-22 are secreted by Th17 cells and have been implicated in tumor progression epithelial ovarian tumors (Winkler et al. 2017). Higher levels of IL-6, IL-1beta, CRP and TNF-alpha are also associated with poorer physical and self-rated health (SRH) measures in post-menopausal women and women with breast cancer (Lekander et al., 2004, Arnberg et al., 2016, Yuan et al., 2017). Based on this evidence, we hypothesized that OC pathogenesis is associated with alterations in the participant’s immune status. Therefore, our first goal was to characterize the peripheral immune phenotype (T lymphocyte populations) and immune function (plasma cytokine levels) in participants with pathologically confirmed OC. The effect of surgical removal of malignant tumors on an individual’s peripheral immune profile is also largely unknown. We hypothesized that removal of an ovarian mass would alter the systemic immune profile. Thus, our second goal was to characterize the peripheral immune phenotype in OC participants following surgical intervention. Greater inflammation may also impact one’s ability to respond effectively to chemotherapy (Koti et al., 2015, Liontos et al., 2021). We hypothesized that participant’s immune profiles, defined by the ratio of Th17:Tregs, will predict chemotherapy response in subjects with OC and immune profiles will negatively correlate with SRH score; thus, determining if SRH could be a promising candidate to be used as an improved screening tool for OC.

Alteration of gastrointestinal and urogenital microbiomes has been described and may contribute to various disease pathophysiology (Kostic et al., 2014, Mukherjee et al., 2018). The relationship between a participant’s inflammatory status and microbial dynamics is evident by unique microbial profiles in some autoimmune conditions (Scher and Abramson, 2011, Rooks and Garrett, 2016). Additionally, microbial profiling of peritoneal fluid has been investigated in other reproductive diseases and reported to be altered in patients with ovarian endometriomas (Lee et al. 2021). We have shown that OC pathogenesis altered the peritoneal microbial environment and that inclusion of a subset of peritoneal microbial features in the clinical assessment (BMI, age, tumor marker levels) increased the diagnostic accuracy for prediction of OC (Miao et al. 2020). Based on our preliminary data, we believe that systemic inflammation in subjects with OC may alter microbial dynamics within the peritoneal cavity and other physiological systems. It is not yet known how these unique peritoneal microbial features may impact an individual’s response to chemotherapy. We hypothesize that unique peritoneal microbial features associated with OC will correlate with participant’s response to chemotherapy.

This paper presents the utility of immune and microbial profiling in predicting response to chemotherapy in participants with OC. We also investigated SRH scores in the context of peripheral inflammation as a potential screening tool for preoperative disease status, “Can participants recognize if they are biologically healthy or not?”. Improving screening methods for overall wellness and understanding platinum-chemotherapy responsiveness will ultimately improve the lives of women with OC and will increase survival rates.