PACM-01 RECEPTOR-COMPLEX–SPECIFIC CD200 ACTIVATION RECEPTOR TARGETING DRIVES COMPARTMENT-SPECIFIC ANTI-TUMOR IMMUNITY IN BREAST CARCINOMA

Abstract

Despite advances in systemic therapy for primary breast carcinoma (BC), up to 30% of patients with advanced disease will develop central nervous system (CNS) metastases. Intracranial progression remains largely incurable and is associated with substantial morbidity. The median survival following diagnosis of brain metastases remains limited, especially for patients with more aggressive forms such as triple negative, as their median survival is just 3.5 months. Treatment for these malignancies remains largely limited to chemoradiation therapy, underscoring the urgent need for therapies capable of generating durable antitumor immunity within both the periphery and CNS. Using breast carcinoma organoid models implanted in the mammary fat pad and cerebellum, we demonstrate that a novel peptide therapy sequence (ARL200Breast), an activating ligand developed by our team, binds to a complex of activation receptors (CD200AR) to elicit robust peripheral antitumor immunity but fails to control CNS tumors. Conversely, a separate sequence (ARL200CNS) effectively suppresses intracranial tumor growth with limited efficacy in the periphery. Mechanistically, ARL200CNS preferentially binds the CD200AR2&3 complex, downregulating NFκB signaling downregulates inhibitory receptors, including CD200R1, PD-1, and PD-L1. We suggest ARL200Breast binds to a different CD200AR complex, driving an alternative immune response. Transcriptomic profiling of treated tumors revealed significant differential gene expression, with over 5,000 genes altered (adjusted p < 0.05), indicating distinct signaling programs activated by each peptide. These findings demonstrate that discrete CD200AR complexes orchestrate compartment-specific immune programs and that the tumor microenvironment may shape therapeutic efficacy. Ongoing studies are evaluating the combination of ARL200 peptides with radiotherapy and Focused Ultrasound, to enhance tumor antigen release and amplify immune priming in both CNS and peripheral settings. Collectively, this work establishes receptor-complex–specific CD200AR targeting as a strategy to generate spatially tailored antitumor immunity and supports further translational development of ARL200-based combination therapies for metastatic breast carcinoma involving the CNS.