Project description:To understand the mechanistic basis of local innate and adaptive immunity against infectious bronchitis virus (IBV) at the molecular level, we examined the gene transcription profile of tracheal epithelial layers at 3 days after infection of chickens with an attenuated IBV-Massachusetts strain. Keywords: Disease State Analysis, Early mucosal immune response, FHCRC 13k chicken array
Project description:Immunological mechanisms of susceptibility to NTM disease are poorly understood. We evaluated innate and antigen-specific adaptive immune responses to Mycobacterium avium complex in individuals with MAC lung disease. We investigated the gene expression changes induced in PBMCs by polyclonal stimulation (anti-CD3, anti-CD28), Mav and Mtb lysates and a peptide pool (MTB300) in individuals with MAC lung disease (MACDZ), and healthy controls (IGRA+ and IGRA-).
Project description:Macrophage-directed immunotherapy has emerged as a promising strategy to eliminate tumors by unleashing phagocytosis, exemplified by blockade of the CD47-SIRPα “don’t eat me” axis. However, despite robust enhancement of phagocytosis, such approaches often fail to generate durable antitumor immunity in solid tumors, highlighting a critical disconnect between innate immune activation and effective T cell responses. Here, we identify PCSK9 as an adaptive resistance factor induced by macrophage immune checkpoint blockade. Tumor-derived PCSK9 promotes lysosomal degradation of MHC-I in macrophages, thereby impairing antigen cross-presentation and limiting CD8⁺ T cell priming. This previously unrecognized mechanism reveals how phagocytosis-targeted therapies can paradoxically suppress adaptive immunity. To overcome this resistance, we engineered bispecific fusion proteins that concurrently target the CD47-SIRPα phagocytosis checkpoint and the PCSK9–MHC-I antigen presentation axis, among which SIRPαD1-αPCSK9 emerged as the optimal format. Dual targeting synergistically enhances macrophage phagocytosis, preserves antigen cross-presentation capacity, and reprograms the tumor microenvironment toward an immunostimulatory state. Consequently, SIRPαD1-αPCSK9 elicits robust activation of both innate and adaptive antitumor immunity, leading to potent tumor control with improved safety. These findings uncover a novel mechanism of resistance to macrophage-centered immunotherapy and establish a rational dual-targeting strategy that bridges phagocytosis and T cell activation, offering a new paradigm for macrophage-driven cancer immunotherapy.