Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma

Abstract

Purpose: Glioblastoma (GBM) patients suffer from a dismal prognosis, with standard of care therapy inevitably leading to therapy-resistant recurrent tumors. The presence of brain tumor initiating cells (BTICs) drives the extensive heterogeneity seen in GBM, prompting the need for novel therapies specifically targeting this subset of tumor-driving cells. Here we identify CD70 as a potential therapeutic target for recurrent GBM BTICs. Experimental Design: In the current study, we identified the relevance and functional influence of CD70 on primary and recurrent GBM cells, and further define its function using established stem cell assays. We utilize CD70 knockdown studies, subsequent RNAseq pathway analysis, and in vivo xenotransplantation to validate the role of CD70 in GBM. Next, we developed and tested an anti-CD70 CAR-T therapy, which we validated in vitro and in vivo using our established preclinical model of human GBM. Lastly, we explored the importance of CD70 in the tumor immune microenvironment (TIME) by assessing the presence of its receptor, CD27, in immune infiltrates derived from freshly resected GBM tumor samples. Results: CD70 expression is elevated in recurrent GBM and CD70 knockdown reduces tumorigenicity in vitro and in vivo. CD70 CAR-T therapy significantly improves prognosis in vivo. We also found CD27 to be present on the cell surface of multiple relevant GBM TIME cell populations. Conclusion: CD70 plays a key role in recurrent GBM cell aggressiveness and maintenance. Immunotherapeutic targeting of CD70 significantly improves survival in animal models and the CD70/CD27 axis may be a viable poly-therapeutic avenue to co-target both GBM and its TIME.

Targeting tumor-associated macrophages for the immunotherapy of glioblastoma: Navigating the clinical and translational landscape

“…The abundance of signal transducer and activator of transcription 3 (STAT3) in GBM has been demonstrated to promote AHR expression and cooperate with HIF-1a to increase CD40 levels, which in turn promoted GBM immune evasion and STAT4-mediated PD-L1 upregulation (42,51,55). Moreover, multiple factors have been implicated in the recruitment and polarization of BMDMs, including slit guidance ligand 2 (SLIT2) (56), Notch1 (57), PTEN (58), NF1 (59), TGF-b (47, 60, 61), M-CSF (47, 60, 61), PD-L2 (62), IL-33 (63), arginase 1 (ARG1) (64), CD47 (65), and CD70 (66). The complex network of interactions that exist between BMDMs and GBM cells within the unique TME needs to be further explored, so as to provide robust guidelines for effective GBM treatment.…”