CD38 overexpression drives glioblastoma progression via L1CAM/ICAM1/JAK-STAT-Driven tumor microenvironment rewiring

Glioblastoma (GBM), a lethal primary brain malignancy, is characterized by dysregulated recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, which promotes tumor growth, and enables immune evasion. Given CD38's role as a multifunctional glycoprotein in hematological malignancies where it regulates immune cell trafficking, we hypothesized that CD38 overexpression in GBM modulates the tumor immune microenvironment.

We utilized the CRISPRa system to enhance CD38 expression in mouse syngeneic GL-261 cells. A murine GBM model was generated by intracranial injection of CD38-overexpressing (CD38-OE) GL-261 cells or CD38 wild-type (WT) or (parental)GL-261 cells into C57BL/6 mice. We utilized serial brain MRIs for tumor progression and assessed overall survival using Kaplan-Meier analysis. We performed multiplex flow cytometry and cytokine assays on brain tumor tissue. Data were analyzed using one-way ANOVA and unpaired t-tests.

Median OS was significantly reduced in CD38-OE mice (26.5 days) versus CD38-WT (35.7 days; p < 0.0001; n = 11/group). Tumor size (in vivo) in CD38-OE vs CD38-WT at day 10 (8.44 mm³ vs. 2.16 mm³; p = 0.0004) and day 17 (34.75 mm³ vs. 8.51 mm³; p = 0.0048). Compared to CD38-WT, CD38-OE tumors showed increased infiltration of glioma-associated macrophages (GAMs) (8.43-fold increase; p < 0.0001), monocytic MDSCs (12.53-fold increase; p < 0.0002), polymorphonuclear MDSCs (15.66-fold increase; p < 0.0001), and T-regs (7.22-fold increase; p < 0.0001). Cytokine profiling indicated elevated CXCL10/IP-10, TIMP-1, and ICAM-1 in CD38-OE tumors.

CD38 overexpression in GBM drives tumor progression by amplifying immunosuppressive TME remodeling, positioning CD38 as a compelling target for further clinical investigation, supported by preliminary efficacy of daratumumab (NCT04922723) in patients with GBM.