Let the Guard Down: cAMP Activators Can Improve Immunotherapy in GBM

Given the limited success in clinical trials of immunotherapies for glioblastoma (GBM), efforts have been made to enhance the efficacy of immunotherapy. GBM is often referred to as “immunologically cold”, characterized by low T-cell infiltration. This can be attributed not only to the low expression of tumor antigens and highly immunosuppressive tumor microenvironment, but also to the blood–brain barrier, which tightly regulates the infiltration of immune cells into the tumor (1). Therefore, enhancing T-cell infiltration to the tumor is likely critical to bolstering antitumor immunity mediated by T cells in GBM. In this issue, Qin, Huang, Li, and colleagues suggest a novel target to enhance T-cell infiltration, consequently boosting the effectiveness of immune checkpoint inhibitor therapy (2).

GBM-derived endothelial cells (GdEC) are thought to be derived from GBM stem cells (GSC) and play a role in vasculature formation, thereby promoting cancer growth and invasion (3). Given that GBM is a highly vascularized tumor, it is crucial to understand the interactions between GdEC and the tumor microenvironment. Through the analysis of human datasets, Qin, Huang, Li, and colleagues find that higher GdEC levels are associated with decreased T-cell infiltration and increased immunosuppressive myeloid cells. In addition, the GdEC signature exhibits a negative correlation with overall survival, suggesting a potential role for GdEC in regulating immune cell infiltration into the tumor and affecting disease outcomes.

Because the VEGF inhibitor bevacizumab has not demonstrated survival benefit in GBM clinical trials (4), Qin, Huang, Li, and colleagues sought a new target to inhibit vasculature formation. Using an in-depth drug screening methodology, they identify two cyclic adenosine monophosphate (cAMP) activators that effectively inhibit tubular structure formation of human GSCs. Mechanistically, the cAMP activators hinder generation of GdEC from GSCs by elevated levels of reactive oxygen species, resulting in increased oxidative stress. Furthermore, cAMP activator treatments are not only effective in inhibiting tumor growth in vitro, but also in vivo, as immune-deficient mice treated with these activators exhibit prolonged survival and reduced angiogenesis within the tumor.

To further investigate the potential of the cAMP activators in modulating immune cell infiltration by reducing GdEC, ibudilast, a compound that can activate cAMP, was administered to immune-competent mice and single-cell RNA sequencing performed. The results reveal an increase in effector T-cell infiltration into the tumor after ibudilast treatment, indicating a possible shift toward an “immunologically hot” tumor phenotype. Indeed, combining cAMP activator treatment with PD-1 blockade significantly extends the survival of mice, with robust memory immune responses observed.

Together, these findings underscore the critical role of vasculature in regulating immune cell infiltration and suggest its potential as a therapeutic target to enhance immunotherapy in GBM. While the current study presents a promising approach of targeting vasculature using cAMP activators, there are several aspects that warrant further investigation. cAMP has immunosuppressive effects, demonstrated by its enhancement of suppressive myeloid function and inhibition of T-cell function (5), which raises important questions. Is this discrepancy in effects attributed to a tumor cell–intrinsic influence of cAMP or is it specific to GBM due to an additional GdEC-inhibiting effect? Further exploration is needed to discern the underlying mechanisms and their implications. Another question of interest concerns the potential combination effect of cAMP activators with VEGF inhibitors. GdEC have been shown to contribute to resistance against VEGF inhibitors in GBM (3). This prompts consideration of whether inhibiting GdEC formation with cAMP activators could synergistically enhance the effectiveness of VEGF inhibitors, offering a novel avenue for improving both antiangiogenic and immunotherapies in GBM. Addressing these questions will deepen our understanding of the intricate interactions involving vasculature, the tumor microenvironment, and immunotherapy responses in GBM.

M.A. Vogelbaum reports grants from NIH; other support from Infuseon, Oncosynergy, Chimerix, Denovo Pharma; personal fees from Olympus; and personal fees from Midatech outside the submitted work; in addition, M.A. Vogelbaum has a patent for “Drug delivery catheter” issued and licensed to Infuseon Therapeutics and a patent for “Drug delivery port” pending. No disclosures were reported by the other authors.

This work was supported by NIH grant, P01 CA245705 (to J.D. Lathia), R35 NS127083 (to J.D. Lathia), F31 CA264849 (to K.E. Kay) and Lerner Research Institute (to J.D. Lathia), and the Case Comprehensive Cancer Center (to J.D. Lathia).