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 CD70’s role 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.
Competing Interest Statement
This work was partly funded by Longbow Therapeutics (company no longer in existence).
Footnotes
↵* These authors made equal contributions to this paper
CONFLICTS OF INTEREST: This work was partly funded by Longbow Therapeutics (company no longer in existence)
TRANSLATIONAL RELEVANCE Glioblastoma is the most common adult malignant brain tumor, and is characterized by a dismal prognosis and poor response to therapy at recurrence. Little-to-no change in standard of care therapy in the last 15 years, despite numerous potential therapies entering clinical trials. Therapeutic failure is largely due to tumor heterogeneity, and a lack of unique tumor associated antigens. Here, we propose CD70 as an immunotherapeutic target in recurrent glioblastoma. CD70 plays a role in key pro-tumorigenic processes and is minimally expressed in normal tissues. We develop a CD70-directed CAR-T cell, which we show to be highly efficacious in extending survival in our intracranial mouse models of recurrent GBM. In addition, we identify CD27 – the receptor for CD70 – on the surface of multiple populations within the tumor immune microenvironment, implying that CD70/CD27 interactions may play a role in the tumor immune microenvironment.