Knight, Joshua A.

Abstract Glioblastoma is the most common primary tumor of the CNS in adults, representing approximately 50% of all gliomas and 15% of primary brain tumors. The current standard of care for GBM is safe maximal surgical resection followed by radiotherapy and concurrent Temozolomide (TMZ), but median survival continues to be 15–16 months. Temozolomide is a second-generation DNA alkylating agent that induces thymine mispairing during DNA replication resulting in tumor cell G2/M phase arrest and autophagy, a standard care of therapy against GBM. While the success of TMZ in clinical trials showed great promise for its overall efficacy, emerging TMZ resistance make us to think more for the combination therapy. CD47, a tumor cell surface marker, plays as “don't eat me signal” through binding its receptor SIRPα on macrophages and the antibody against CD47, which blocks interactions of CD47 with SIRPα, has been shown to lead to tumor destruction. Furthermore, CD47 is a prognostic marker as its expression predisposes cancer patients to a poorer survival outcome. This has significant clinical implications since approximately more than 80% of patients with the most GBMs, overexpress CD47. Overexpression of CD47 is also associated with a decreased probability of survival in clinical cohorts of GBM. Our work and that of others demonstrate that CD47 blockade enables tumor cell phagocytosis by antigen presenting cells (APC), establishing this molecule as a viable therapeutic target in GBM. We additionally investigated the combinatorial effect of CD47 blockade with temozolomide. DNA alkylating agents induce sporadic tumor cell necrosis associated with the extracellular release of damage associated molecular patterns (DAMPs) such as calreticulin, a pro-phagocytic protein whose interaction with low density lipoprotein receptor-related protein 1 (LRP1) facilitates recognition by professional antigen-presenting cells (APCs) and acts as a critical molecular component in promoting immunogenic cell. Our results showed that tumor cell treatment with temozolomide induces plasma membrane expression of calreticulin. Combination therapy resulted in amplified tumor cell phagocytosis and antigen presentation by APC. In addition, preclinical assessment of combination therapy in a syngeneic murine model of GBM resulted in significantly improved survival, characterized by increased intra-tumor penetration of APC cells. These results suggest that the combination of CD47 blockade with temozolomide may enhance tumor immunogenicity, and can improve clinical outcomes demonstrated by mono-therapeutic approaches with conventional chemotherapy. Citation Format: Yaqing Qie, Christina Von Roemeling, Yuanxin Chen, Kevin Shih, Xiujie Liu, Wen Jiang, Joshua Knight, Charles Chan, Irving Weissman, Betty Kim. CD47 blockade with temozolomide can enhance the therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-208. doi:10.1158/1538-7445.AM2017-LB-208

Abstract Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. Agents that specifically target crucial metabolic enzymes utilized by cancer are been actively investigated. However, it is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. Here, we show for the first time that inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in fatty-acid synthesis and a potential prognostic marker for human cancers, increases the immunogenicity of poorly immunogenic tumors. The enhanced immune activation is accompanied by upregulated endoplasmic reticulum (ER) stress and is dependent on the translocation of ER protein calreticulin to the tumor cell surface. Inhibition of SCD1 increased both recruitment and activation of immune cells in vivo, which when combined with PD-1 blockade resulted in potent and durable anti-tumor T cell responses. Together, our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapy. Citation Format: Christina Anna Elizabeth Von Roemeling, Thomas Caulfield, Yaqing Qie, Derek C. Radisky, Xiujie Liu, Yuanxin Chen, Joshua Knight, John Copland, Betty Kim. Blockade of stearoyl CoA desaturase 1 promotes immunogenic clearance of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-189. doi:10.1158/1538-7445.AM2017-LB-189