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How Cancer Cell Death Can Thwart Therapy

Posted by on Tuesday, December 4, 2018 in Discoveries.

Apoptosis is a mechanism of cell death that occurs in normal tissues as part of natural cell turnover and remodeling. Apoptotic cells are cleared by efforcytosis, a specialized form of phagocytosis mediated by MerTK, a receptor tyrosine kinase expressed by many phagocytic cells. MerTK recognizes a combination of ligands, such as Gas6, in combination with phosphatidylserine, which is expressed on the surface of apoptotic cells.  Activation of MerTK leads to signaling within the phagocyte that suppresses the expression of pro-inflammatory mediators while promoting expression of immunosuppressive ones. The result is clearance of apoptotic cells without an accompanying inflammatory response. Although this process is highly beneficial in healthy tissues, it can be a problem in cancer therapy because many anti-cancer agents induce apoptosis in tumor cells. Subsequent efferocytosis of these cells leads to suppression of the immune response to the cancer. This phenomenon was confirmed by Vanderbilt Basic Sciences investigator Rebecca Cook and her laboratory during studies of the MMTV-Neumouse breast cancer model. MMTV-Neumice develop breast tumors as a result of overexpression of Neu, which is homologous to the human breast cancer-associated HER2 protein. Treatment of the mice with lapatinib, a HER2 inhibitor, induces apoptosis in the tumors. The researchers confirmed that this apoptotic response led to efferocytosis of the dead cells, and they observed hallmarks of immunosuppression in the tumors. This finding led them to hypothesize that treatment of the mice with both imatinib and BMS-77607 (BMS), a MerTK blocker, would lead to apoptosis without efferocytosis, resulting in necrosis of the tumor cells and a pro-inflammatory response. They were surprised, however, to find that although necrosis did result following treatment with imatinib and BMS, the immunosuppressed state remained. Further investigation revealed that necrosis induced by imatinib plus BMS led to secretion of the pro-inflammatory cytokine interferon- (IFN)-γ. However, one outcome of IFN-γ secretion was an increase in levels of indolamine-2,3-dioxygenase (IDO-1), an enzyme known to promote immunosuppression and resolution of inflammation. The researchers hypothesized that high levels of IDO-1 were helping to maintain immunosuppression despite the presence of necrotic cells in the tumors. Consistently, when they treated mice with imatinib, BMS, and epacadostat, an inhibitor of IDO-1, they observed a reduction of immunosuppression accompanied by a much greater decrease in tumor growth and lung metastasis than when mice were treated with any combination of just one or two of the drugs. The results suggest that, at least in this breast cancer model, treatment-induced apoptosis leads to efferocytosis-dependent immunosuppression that can impede the effects of therapy. Furthermore, simple blockade of efferocytosis may not be adequate to counteract this effect. Clearly, the effects of treatment on cancer cells and their immediate environment is complex, and further work will be required to determine the best approach to this problem for each kind of cancer. The work is published in Cancer Research [T.A. Werfel, et al. (2018) Cancer Res., published online November 9, DOI: 10.1158/0008-5472.CAN-18-1106

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