Myeloid-derived Suppressor Cell Heterogeneity Comprises a Sex-specific Therapeutic Target for Glioblastoma

Portrait of Justin Lathia

A study led by Justin D. Lathia, PhD (Bayik et al., Cancer Discovery, 2020) and conducted in collaboration with multiple Case Comprehensive Cancer Center member investigators (Ahmad M. Khalil, PhD; Tae Hyun Hwang, PhD; Manmeet S. Ahluwalia, MD and Feixiong Cheng, PhD) identified sex differences in anti-tumor immune response, which served as the basis for a new therapeutic strategy against glioblastoma (GBM). While previous epidemiological research has shown that males are predisposed to GBM, the most common primary malignant brain tumor; the new findings uncover sexual dimorphism in immune-suppressing myeloid cell subset, prevalence and localization as a contributor of disease pathology. These immunological differences further informed the use of drug candidates for personalized immunotherapy accounting for patient sex. These studies are part of a larger Case Comprehensive Cancer program on sex differences in GBM co-led by Drs. Lathia and Jill Barnholtz-Sloan, PhD.

The study, supported by an active NIH R01 awarded to Dr. Lathia, F32 and the Case Comprehensive Center T32 Cancer Biology Training Grant to the first author, Defne Bayik, PhD, reported that monocytic myeloid-derived suppressor cells (mMDSCs) accumulated at higher rates in male tumors in preclinical models, an observation confirmed in patients with GBM. The researchers determined that mMDSCs are actively proliferating and tested the chemotherapeutic fludarabine, a treatment strategy turned out to be only effective in males. mMDSCs along with the related granulocytic myeloid-derived suppressor cell subset (gMDSCs) are known to suppress immune response across many cancers, though their distinct function had not been explored in GBM. The team observed that gMDSCs were increased in the systemic circulation of female mice with tumors. Analysis of repurposable drug candidates in collaboration with Feixiong Cheng, PhD, based on the distinct expression profile of gMDSCs and subsequent validation in preclinical models identified IL-1β as an effective immunotherapeutic strategy in females. High gMDSC and IL-1β signatures correlated with poor prognosis of female patients with GBM, supporting the clinical relevance of these observations.

“These findings highlight the importance of considering sex as a biological variable for development of effective immunotherapeutic strategies against GBM as well as other cancers. We look forward to translating findings of this study through clinical trials with the goal of improving patient outcome,” said Lathia, co-Leader of the Molecular Oncology Program at the Case Comprehensive Cancer Center, co-director of the Cleveland Clinic Center for Excellence in Brain Tumor Research and Therapeutic Development and Leader of the Brain Tumor Initiative.