Abstract A49: A dual blockade of N-CoR2- and immune checkpoints induces complete remissions in treatment-refractory tumors

Background: The majority of human malignant tumors are resistant or only partially respond to conventional chemotherapy (C/T) or immunotherapy (I/T) such as immune checkpoint inhibitors (ICIs). Irrespective of the treatments, efficient tumor-cell killing requires amplification of inflammatory signaling, which, however, is tightly regulated by various “checkpoint” mechanisms evolved by epithelial cells to prevent excessive tissue damage induced by virus and immune attack. Novel approaches to disable theses conserved and cell-intrinsic inflammation checkpoints may provide breakthrough and “tumor-agnostic” strategies to circumvent the innate treatment resistance to unleash the full potential of C/T and I/T in treatment-refractory and highly lethal malignant tumors, such as triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), and glioblastoma multiform (GBM). Materials and Methods: We designed and conducted integrated genomic and proteomic screening combined with molecular and functional studies to identify conserved anti-inflammatory pathways that mediate innate and cell-intrinsic resistance to C/T and I/T agents. Preclinical studies were used to validate a gene therapy strategy to disable the inflammation-checkpoint identified from this process. Results: We uncovered that the cytotoxic and immunogenic death induced by C/T and I/T agents is constrained by repression of a toll-like receptor-2 (TLR-2)/TLR-3- and NF-kB-induced interferon regulatory factor-1 (IRF-1) and interferon (IFN)-gamma anti-viral response program in various malignant tumor cells, including breast cancer, PDAC and GBM. Loss- and gain-of-function studies implicated that co-repressor-2 (N-CoR2) co-translocated with NF-kB p50 into cell nuclei in response to therapy, wherein it serves as an epigenetic checkpoint of this inflammation program by mediating a histone deacetylase-dependent chromatin remodeling and repression of a specific panel of proinflammatory and proapoptotic genes. Thus, high N-CoR2 expression predicts treatment refractoriness and poor prognosis in neoadjuvant or adjuvant-treated breast cancer patients. Blockade of the epigenetic checkpoint function of N-CoR2 by a small decoy of N-CoR2 hypersensitized malignant cells to assorted C/T agents, death ligands, and IFN-gamma. Consistently, intratumoral delivery of the N-CoR2 checkpoint blockade dramatically potentiated systemic C/T and ICI therapies, including anti-PD-1 and anti-CTLA-4 antibodies, and completely halted tumor growth or induced remissions in orthotopic and patient-derived xenograft models of TNBC and GBM. Conclusion: Our findings suggest that malignant tumors can access intrinsically conserved anti-inflammatory mechanisms that enable them to escape from C/T and I/T. As such, strategies that can override this defense program constitute novel antitumor gene therapies that may be applied to overcome resistance in treatment-refractory tumors and improve patient prognosis. Citation Format: Kelvin Tsai, Valerie M. Weaver. A dual blockade of N-CoR2- and immune checkpoints induces complete remissions in treatment-refractory tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A49.