Cancer-induced activation of CD11b+Gr-1+ cells predispose hosts to antibody-independent anaphylactoid-type reactions (36.5)

Abstract

Abstract Cancer can induce expansion of CD11b+Gr-1+ myeloid cells, attributed to immune suppression. We noted tumor-activation of these cells further correlated with predisposition for anaphylactoid-type reactions in mice bearing 4T1 mammary carcinomas, which induces strong CD11b+Gr-1+ expansion. To test this hypothesis, 4T1-tumor bearing (4T1+) mice were challenged with recombinant adenoviral vector (rAd), previously shown to activate myeloid lineage cells. When challenged with a single intravenous dose of rAd, 4T1+ mice succumbed to acute anaphylactoid-type reactions. In contrast, minimal responses were seen in rAd treated mice implanted with the related cell line, 66cl4, which do not induce CD11b+Gr-1+ cells. Liposome depletion prior to rAd challenge protected 4T1+ mice, whereas, passive transfer of CD11b+Gr-1+ cells from 4T1+ mice was sufficient to convey susceptibility for anaphylactoid reactions in normal mice. Metabolic pathways were upregulated for nitric oxide and leukotrienes in the 4T1-induced CD11b+Gr-1+ cells. Pre-treating 4T1+ mice with inhibitors of NO-synthetase and leukotrienes inhibited rAd-induced anaphylaxis. Thus, malignant tumor growth can alter CD11b+Gr-1+ myeloid cells, rendering hosts susceptible to anaphylactoid-type reactions. Importantly, there was no requirement for pre-existing Ag-specific IgE or IgG. This reflects clinical reports in which cancer patients undergo treatment-induced anaphylactoid responses in absence of pre-exposure and may provide insight for modeling alternative pathways induced by direct activation of inflammation- or tumor-modified myeloid cells. * Funded by the Schering-Plough Research Institute