Treatment options remain limited for women with ovarian cancer as they usually do not respond well to a new type of therapy that uses the patient’s own immune system to fight cancer. This is despite the fact that ovarian cancer often has high numbers of T cells, an immune cell that has an ability to kill cancer cells. It is now known that T cells that are found in ovarian cancer are often stressed due to low amounts of oxygen, nutrients, and other critical factors. This stressed nature impairs the ability of the T cell to fight cancer. Therefore, identifying the ways through which T cells experience stressed conditions may lead to the development of new immune system-based therapeutic strategies for ovarian cancer. To this end, we have discovered a mutation in a molecule found in T cells that is associated with an improved outcome for ovarian cancer patients. Interestingly, this molecule appears to function within a poorly characterized stress-response system within T cells. Our study is therefore designed to understand the connection between this molecule and T cell activity in ovarian cancer, as we have found that T cells in which this molecule is removed have increased anti-tumor activity and delay disease progression. Thus, we expect that the completion of this work will drive the development new T cell-based therapeutic strategies in which stress response pathways have been altered in order to significantly improve the outcome of women with ovarian cancer.
Kyle K Payne, PhD, is an Assistant Professor of Medicine, Section of Cancer Immunotherapy, at the Robert Wood Johnson Medical School and is a Resident Member of the Cancer Institute of New Jersey. Dr. Payne is a trained immuno-oncologist, where he has spent the first 10 years of career focused on dissecting mechanisms immune suppression in the tumor microenvironment. During his PhD training, under the supervision of Dr. Masoud Manjili at Virginia Commonwealth University, Dr. Payne largely focused on targeting the immunosuppressive activity of myeloid-derived suppressor cells. He demonstrated that these cells could be functionally reprogrammed into immunostimulatory ‘antigen-presenting-like’ cells to promote antitumor T cell activity in breast cancer (J Immunol., 2011; Payne et al. Breast Cancer Res Treat, 2013; Payne et al., Kmieciak*, Basu*, Payne* et al. J Leukoc Biol., 2018), thereby unveiling key features of myeloid-derived suppressor cell biology.
Following the completion of his dissertation, Dr. Payne joined the laboratory of Dr. Jose Conejo-Garcia to pursue his postdoctoral training, first at the Wistar Institute/The University of Pennsylvania, and then at the H. Lee Moffitt Cancer Center. During this time, Dr. Payne investigated the mechanism of unrelenting expression of PD-1 on the surface of tumor-infiltrating T cells in ovarian cancer. He found that the genomic organizer, SATB1, functions as a repressor of PD-1 through orchestration of NuRD complexes within Pdcd1 regulatory regions. In contrast, tumor-derived TGF-beta signaling was found to decrease SATB1 expression through SMAD occupancy of the Satb1 promoter, thus defining tumor microenvironmental TGF-beta as a driver of PD-1 expression in ovarian tumor beds (Stephens*, Payne* et al. Immunity, 2017). To complete his postdoctoral training, Dr. Payne subsequently identified butyrophilin 3A1 (BTN3A1) as a T cell regulator in ovarian cancer. Dr. Payne’s research unveiled that BTN3A1 is overexpressed in high-grade serous ovarian carcinoma, where it suppresses alpha/beta T cells through an N-linked glycosylation CD45-dependent mechanism. In preclinical studies, Dr. Payne found that targeting this molecule with clinical-grade fully human antibodies released alpha/beta T cells from BTN3A1-mediated suppression. Intriguing, these antibodies concurrently promoted BTN3A1-dependent activation of Vgamma9 Vdelta2 T cells to acquire cytotoxic activity against tumor cells (Payne, et al. Science, 2020), thus creating new therapeutic approaches for the management of ovarian cancer.
Dr. Payne is a member of the American Association of Immunologists (AAI), the Society for Immunotherapy of Cancer, and the American Association for Cancer Research. He has served as an ad hoc reviewer and invited guest editor for scientific journals. He is a former American Cancer Society Postdoctoral Fellow, and has previously been supported by a University of Pennsylvania NRSA training grant, as well as an AAI Careers in Immunology Fellowship.