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.

24