JAM-A functions as a female microglial tumor suppressor in glioblastoma

Abstract

Background Glioblastoma (GBM) is the most aggressive primary brain tumor and has a dismal prognosis. Previously, we identified that junctional adhesion molecule-A (JAM-A), a cell adhesion molecule, is highly elevated in human GBM cancer stem cells and predicts poor patient prognosis. While JAM-A is also highly expressed in other cells in the tumor microenvironment, specifically microglia and macrophages, how JAM-A expression in these cells affects tumor growth has yet to be determined. The goal of this study was to understand the role of microenvironmental JAM-A in mediating GBM growth. Methods Male and female wild-type (WT) and JAM-A-deficient mice were transplanted intracranially with the syngeneic glioma cell lines GL261 and SB28 and were assessed for differences in survival and microglial activation in tumors and in vitro. RNA-sequencing was performed to identify differentially regulated genes among all genotypes, and differences were validated in vitro and in vivo. Results We found that JAM-A-deficient female mice succumbed to GBM more quickly compared to WT females and JAM-A-deficient and male WT mice. Analysis of microglia in the tumors revealed that female JAM-A-deficient microglia were more activated, and RNA-sequencing identified elevated expression of Fizz1 and Ifi202b specifically in JAM-A-deficient female microglia. Conclusions Our findings suggest that JAM-A functions to suppress pathogenic microglial activation in the female tumor microenvironment, highlighting an emerging role for sex differences in the GBM microenvironment and suggesting that sex differences extend beyond previously reported tumor cell-intrinsic differences.

Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

“…Further interrogation into the oncogenic phenotype revealed that microglia are more activated in JAM-A deficient females and that the expression of anti-inflammatory genes in female microglia increases when JAM-A is knocked out. In line with a putative anti-inflammatory phenotype, JAM-A deficient female microglia are more phagocytic and enhance the proliferation of GL261 glioma cells in vitro [68]. These data also suggest that while anti-inflammatory microglia can suppress anti-cancer immune defenses, they may also release factors to drive glioma proliferation directly.…”

“…When JAM-A is deleted in male and female mice, male mice exhibited a slight survival advantage. Knocking out JAM-A did not significantly alter male survival but significantly reduced female mouse survival [68]. Further interrogation into the oncogenic phenotype revealed that microglia are more activated in JAM-A deficient females and that the expression of anti-inflammatory genes in female microglia increases when JAM-A is knocked out.…”

“…However, recent work demonstrates that junctional adhesion molecule A (JAM-A) may function as a female microglial tumor suppressor. In their studies, Turaga et al demonstrated that female mice live longer after intracranial injection of syngeneic GL261 murine glioma cells [68]. When JAM-A is deleted in male and female mice, male mice exhibited a slight survival advantage.…”

Targeting Opposing Immunological Roles of the Junctional Adhesion Molecule-A in Autoimmunity and Cancer

“…Altogether, these studies suggest that although JAM-A expressed by tumor cells may have a protective role on progression of cancer, JAM-A antagonism could enhance immune response against these abnormal cells by possibly facilitating leukocyte infiltration into tumors and DC egress to LNs (see Figure 2). Nevertheless, in a recent study, JAM-Adeficient female mice developed a more aggressive phenotype of brain tumor in comparison with WT females and JAM-Adeficient and WT males (74). This study highlights the impact of other factors, such as sex difference, in the therapeutic effects that JAM-A blockade might promote in the development of tumors and demonstrates the complexity and challenges involved in the potential development of a JAM-A-targeted drug for cancer treatment.…”

Microglia in Health and Disease: The Strength to Be Diverse and Reactive

“…Interestingly, microglia diversity associated with brain tumors, and specifically in GBM, has been investigated also taking into account gender specificities. Turaga et al (2020) , while conducting a study regarding the implication of junctional adhesion molecule-A (JAM-A), noticed a poorer prognosis in GBM implanted female JAM-A deficient mice when compared to the corresponding implanted males. Notably, the authors reported an upregulation of the anti-inflammatory genes Fizz1 and Ifi202b in microglia from female JAM-A deficient mice compared to their male counterparts ( Turaga et al, 2020 ).…”