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Treatment-induced tumor cell apoptosis and secondary necrosis drive tumor progression in the residual tumor microenvironment through MerTK and IDO-1


Werfel TA , Elion DL , Rahman B , Hicks DJ , Sanchez V , Gonzalez-Ericsson PI , Nixon MJ , James JL , Balko JM , Scherle P , Koblish HK , Cook RS , . Cancer research. 2018 11 9; ().


Efferocytosis [phagocytic apoptotic cell (AC) clearance] removes AC before they undergo secondary necrosis and leak inflammation-inducing intracellular contents. Efferocytosis concurrently increases immunosuppressive cytokines and leukocytes, limiting tissue damage, promoting tolerance to AC-derived antigens, and maintaining tissue homeostasis. Thus, tumor cell efferocytosis following cytotoxic cancer treatments could have deleterious consequences in tumor residual disease (RD). We report here that efferocytosis clears tumor AC in RD of lapatinib-treated HER2+ mammary tumors, increasing immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), regulatory T cells (TRegs), and metastasis. Although efferocytosis blockade caused secondary AC necrosis and induced interferon (IFN)-γ, tumor MDSC, TRegs, and immunosuppressive cytokines remained prevalent due to IFNγ-induced indoleamine-2,3-dioxegenase (IDO)-1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO-1 in tumor RD decreased AC-induced and NC-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of cases. This suggests that AC and NC promote tumor ‘homeostasis’ and progression via efferocytosis.