“Leveraging sex differences in glioblastoma immune response for next-generation brain tumor therapies”
Defne Bayik Watson Ph.D.
Research Associate, Cleveland Clinic Lerner, OH, United States
Dr. Defne Bayik is a cancer immunologist focused on uncovering host regulatory pathways as targets for brain tumor immunotherapy. She started her graduate training in Bilkent University Department of Molecular Biology and Genetics in 2010 after completing her undergraduate education in the same department. Dr. Bayik received her PhD in 2016 through the Graduate Partnership Program between the National Institutes of Health, USA and Bilkent University. Working under the mentorship of Drs. Dennis M. Klinman and Ihsan Gursel, she delineated the distinct differentiation pathways of immature myeloid cells to inflammatory and immunosuppressive macrophages in cancer and autoimmunity. In 2017, Dr. Bayik joined the laboratory of Dr. Justin D. Lathia at the Cleveland Clinic as a postdoctoral fellow, where she gained experience in neuro-oncology and translational cancer immunotherapy research. Under Dr. Lathia’s mentorship, she demonstrated that sex differences in immunosuppressive myeloid cells determine glioblastoma progression and therapeutic response. These results were published in Cancer Discovery in 2020 and constituted the basis of Dr. Bayik’s K99/R00 Pathway to Independence Award. Dr. Bayik is currently a Research Associate in Cleveland Clinic. Her ongoing research investigates the molecular basis of sex differences in anti-tumor immune response and mechanisms of myeloid cell immunosuppression in glioblastoma.
Glioblastoma (GBM) is the most common primary malignant brain tumor with a median survival of up to 20 months. Males constitute the majority of GBM patients and have a worse outcome than females, pointing a sexual dimorphism in disease incidence and prognosis. Immunotherapies, which have shown promise in various solid tumors, have had limited success in improving the outcome of GBM patients. This is in part due to a potently immunosuppressive tumor microenvironment that facilitates progression and therapeutic resistance of GBM. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that associate with poor prognosis of GBM patients. MDSCs are classified into two subsets as monocytic (mMDSC) and granulocytic (gMDSC), but the distinct role of individual subpopulations is not well-defined. Using preclinical models and patient specimens, we demonstrated that MDSC subsets can drive GBM in a sex-specific manner. mMDSCs infiltrate male tumors effectively, while gMDSCs expand in peripheral circulation of female mice. Aligned with this observation, targeting proliferating mMDSCs with chemotherapeutic agents only provided survival benefit to male mice with tumors. In contrast, systemic depletion of gMDSCs or inhibition of their activity with IL-1β neutralizing antibodies improved survival outcome of female mice. These differences in MDSC subset activity were informed by epigenetic programming. Assessment of the open chromatin regions indicated that cell adhesion genes are more accessible in mMDSCs compared to gMDSCs. Mouse and human mMDSCs had higher surface integrin β1 levels compared to gMDSCs. Furthermore, integrin β1 blockade abrogated pro-tumorigenic function of mMDSCs by reprogramming the tumor immune microenvironment. Collectively, our findings indicate that MDSC subset variation represents an opportunity for improved immunotherapy efficacy by accounting for sex as a biological variable and modulation of immunosuppressive myeloid cells by leveraging differences in adhesion mechanisms represents a potential immunotherapeutic option for GBM.
Date-Time:Wednesday, Dec 1, 2021 15:30
Host: Doç. Dr. Işık Yuluğ
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All interested are cordially invited