Abstract 5077: Engineering dendritic cell-derived exosomes forbrain metastases immunotherapy

Abstract

Abstract Brain metastases (BrMs) represent an unmet challenge for the therapy of most aggressive cancers owing to the extremely poor survival and the limited efficacy of available therapies. Currently, NO curative therapy for breast cancer BrM (BCBrM) is available and we urgently need to develop new and effective therapies. Immune checkpoint therapies (ICT) have revolutionized cancer treatment, but are generally unsuccessful in treating BrMs, including BCBrM. A crucial reason for this is the unique brain immune microenvironment with low antigen exposure/presentation in BrMs and fewer antigen-specific T cells in the brain parenchyma. The priming and activation of antigen-specific T cells require professional antigen-presenting dendritic cells (DCs) for effective antigen presentation through multifaceted communication between DCs and T cells by direct intercellular contact and indirect distant communication via exosomes and other means. DC-derived exosomes (DCEXs) carry functional MHC-I/peptide complexes (pMHC-I) and costimulatory molecules, hence facilitating systemic T cell immune responses. DCEXs have been developed as immunotherapies which exhibit advantages over DC-based immunotherapies. However, DCEXs in ongoing clinical trials showed limited efficacy. We found that increased non-receptor protein tyrosine phosphatase SHP1, a DC-intrinsic inhibitory checkpoint, in monocyte-derived DCs (MoDCs) ex vivo led to DC exhaustion that limits DCEXs function resulting in poor systemic T cells stimulation in vivo. To improve DCEXs functions, we developed next-generation DCEXs by genetic knockout of SHP1 in DCs from which DCEXs (iSHP1-DCEXs) were isolated. Remarkably, the modified iSHP1-DCEXs exhibited significantly increased pMHC-I expression and more effectively improved T cell proliferation compared to control DCEXs, indicating a greater capacity of antigen presentation of engineered iSHP1-DCEXs. In the EO771-OVA mammary tumor cells-bearing mouse model, iSHP1-DCEXs treatment greatly increased tumor infiltration of OVA antigen-specific CD8+ T (OT-1) cells resulting in tumor inhibition and prolonged mouse survival, indicating that iSHP1-DCEXs elicited an effective and specific antitumor immunity in vivo. Moreover, combining iSHP1-DCEXs with anti-PD1 Ab yielded a strong syngenetic therapeutic response in mice bearing the anti-PD1-resistant EO771 tumors, as indicated by delayed tumor growth and prolonged survival. importantly, iSHP1-DCEXs also significantly increased tumor-infiltrating antigen-specific T cells and synergized with PD-1 Ab leading to tumors clearance in mice bearing the B16-GMCSF melanoma. To further test the iSHP1-DCEXs effect in BCBrM, we co-injected EO771-OVA and iSHP1-DCEXs into mice and found that iSHP1-DCEXs inhibited BrM. Together, the engineered iSHP1-DCEXs offer a promising option to generate a potent antigen-specific T cell immune response for BCBrM inhibition. Citation Format: Hao-Nien Chen, Xiangliang Yuan, Yimin Duan, Yi Xiao, Shao-Ping Yang, DIhua Yu. Engineering dendritic cell-derived exosomes forbrain metastases immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5077.