Exogenous remodeling of the lung macrophage microenvironment protects against infectious consequences of bone marrow ablative chemotherapy

Infection is the single greatest threat to survival during cancer chemotherapy because of depletion of bone marrow derived immune cells. In the absence of phagocytes such as neutrophil, vaccine-induced humoral and cellular anti-pathogen immunity are compromised. Using a model of vaccine-induced protection against lethal P. aeruginosa pneumonia in the setting of chemotherapy-induced neutropenia, we found a population of resident lung macrophages in the immunized lung that mediated protection in the absence of neutrophils, bone marrow derived monocytes, or antibodies. These vaccine-induced macrophages (ViMs) expanded after immunization, locally proliferated, and were closely related to alveolar macrophages (AMs) by surface phenotype and gene expression profiles. By contrast to AMs, numbers of ViMs were stable through chemotherapy, show enhanced phagocytic activity, and prolonged survival of neutropenic mice from lethal P. aeruginosa pneumonia upon intratracheal adoptive transfer. Thus, induction of ViMs by tissue macrophage remodeling may become a framework for new strategies to activate immune-mediated reserves against infection in immunocompromised hosts. We compared the global transcription profiles of three different populations of resident lung macrophages in mice following intranasal immunization with a live-attenuated Pseudomonas aeruginosa vaccine (strain PAO1ΔaroA) with or without cyclophosphamide (CY) treatment. Macrophages were isolated from collagenase-digested whole lung at 4 weeks after 3 weekly doses of immunization with or without CY (150mg/kg/dose i.p.) on days -6, -4, -2 of harvest. Overall, there were three treatment groups: Control (unvaccinated, no CY treatment), Vac only (vaccinated but not treated with CY), or Vac+CY (vaccinated and CY-treated). Five mice from each treatment group were pooled and treated as a single sample for microarray analysis to guarantee enough number of cells for each assay. Each treatment group consisted of biologically independent triplicates which were processed in 3 independent experiments.