Advance-CTR

Advance-CTR Pilot Projects Program (Cycle 6)

"Immunologic responses to chemotherapy in high grade serous ovarian cancer"

Outcomes for high grade serous ovarian cancer (HGSOC) patients have remained dismal due to poor diagnostics and the inevitable development of chemotherapy resistance with recurrent disease. In order to better tailor treatment approaches and uncover opportunities for novel treatments, we need to understand factors in the tumor microenvironment that mediate chemotherapy response/resistance. Despite poor response rates of ovarian cancer patients to currently studied immunotherapies, recent studies have shown that immune-related gene expression profiles serve as biomarkers of response to chemotherapy and clinical outcomes in solid tumors, including ovarian cancer. Moreover, the interplay between chemotherapy and the immune system is evident in the multifactorial ways chemotherapy impacts the tumor immune microenvironment. As such, harnessing ovarian tumor immune responses to chemotherapy to improve patient responses may offer an alternative approach to immunotherapy than has been previously explored. We hypothesize that immunologic changes occurring in response to chemotherapy can be exploited to combat the development of chemoresistance and that serum immune factors can predict patient responses to chemotherapy. Our preliminary data support our hypothesis and have identified significantly longer overall survival and time to progression in patients with increased tumor and circulating levels of immune co-receptors, as well as chemotherapy-induced changes in immune signatures that may mediate chemoresistance in patient tumors and HGSOC cell lines.

This research program will move forward with two aims: Aim 1 will identify novel immune therapeutic targets following chemotherapy treatment by performing a transcriptomic-based immune modeling analysis to determine the most significant tumor immune microenvironment changes following NACT, as well as their relationship with chemotherapy response and progression-free survival (PFS). Aim 2 will identify circulating prognostic biomarker signatures of chemotherapy response and survival by measuring levels of cytokines and candidate soluble tumor factors in patient serum throughout the course of chemotherapy treatment. Thus, this project will make groundbreaking headway in understanding the complexity of intratumoral and circulating immunologic effects of chemotherapy, with the ultimate goal of identifying immunologic factors and pathways that can be leveraged as novel targets following chemotherapy exposure, as well as the development of prognostic and treatment guiding biomarkers.

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