Inducing regulated necrosis and shifting macrophage polarization with anti-EMMPRIN antibody (161-pAb) and complement factors

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Nizar Hijaze¹  Max Ledersnaider²  Elina Simanovich²  Sameer Kassem¹  Michal A. Rahat² 

[1] Department of Internal Medicine A, Carmel Medical Center;Immunotherapy Laboratory, Carmel Medical Center;Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology

关键词: dsRNA;    EMMPRIN/CD147;    IFN response;    macrophage polarization;    regulated necrosis;    tumor microenvironment;   

DOI  :  10.1002/JLB.3A0520-333R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Treatment of solid tumors is often hindered by an immunosuppressive tumor microenvironment (TME) that prevents effector immune cells from eradicating tumor cells and promotes tumor progression, angiogenesis, and metastasis. Therefore, targeting components of the TME to restore the ability of immune cells to drive anti-tumoral responses has become an important goal. One option is to induce an immunogenic cell death (ICD) of tumor cells that would trigger an adaptive anti-tumoral immune response. Here we show that incubating mouse renal cell carcinoma (RENCA) and colon carcinoma cell lines with an anti-extracellular matrix metalloproteinase inducer polyclonal antibody (161-pAb) together with complement factors can induce cell death that inhibits caspase-8 activity and enhances the phosphorylation of receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase-like domain (MLKL). This regulated necrotic death releases high levels of dsRNA molecules to the conditioned medium (CM) relative to the necrotic death of tumor cells induced by H 2 O 2 or the apoptotic death induced by etoposide. RAW 264.7 macrophages incubated with the CM derived from these dying cells markedly enhanced the secretion of IFNβ, and enhanced their cytotoxicity. Furthermore, degradation of the dsRNA in the CM abolished the ability of RAW 264.7 macrophages to secrete IFNβ, IFNγ-induced protein 10 (IP-10), and TRAIL. When mice bearing RENCA tumors were immunized with the 161-pAb, their lysates displayed elevated levels of phosphorylated RIPK3 and MLKL, as well as increased concentrations of dsRNA, IFNβ, IP-10, and TRAIL. This shows that an antigen-targeted therapy using an antibody and complement factors that triggers ICD can shift the mode of macrophage activation by triggering regulated necrotic death of tumor cells.

【 授权许可】

CC BY