Abstract
Efferocytosis is the process by which apoptotic cells are cleared from tissue by phagocytic cells. The removal of apoptotic cells prevents them from undergoing secondary necrosis and releasing their inflammation-inducing intracellular contents. Efferocytosis also limits tissue damage by increasing immunosuppressive cytokines and leukocytes and maintains tissue homeostasis by promoting tolerance to antigens derived from apoptotic cells. Thus, tumor cell efferocytosis following cytotoxic cancer treatment could impart tolerance to tumor cells evading treatment-induced apoptosis with deleterious consequences in tumor residual disease. We report here that efferocytosis cleared apoptotic tumor cells in residual disease of lapatinib-treated HER2+ mammary tumors in MMTV-Neu mice, increased immunosuppressive cytokines, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). Blockade of efferocytosis induced secondary necrosis of apoptotic cells, but failed to prevent increased tumor MDSCs, Treg, and immunosuppressive cytokines. We found that efferocytosis stimulated expression of IFN-γ, which stimulated the expression of indoleamine-2,3-dioxegenase (IDO) 1, an immune regulator known for driving maternal-fetal antigen tolerance. Combined inhibition of efferocytosis and IDO1 in tumor residual disease decreased apoptotic cell- and necrotic cell-induced immunosuppressive phenotypes, blocked tumor metastasis, and caused tumor regression in 60% of MMTV-Neu mice. This suggests that apoptotic and necrotic tumor cells, via efferocytosis and IDO1, respectively, promote tumor 'homeostasis' and progression. SIGNIFICANCE: These findings show in a model of HER2+ breast cancer that necrosis secondary to impaired efferocytosis activates IDO1 to drive immunosuppression and tumor progression.
Highlights
In untransformed tissues, the immune system responds to apoptotic cells (AC) in complex ways that support wound healing, suppress inflammation, limit immune-mediated tissue damage and prevent autoimmunity [1, 2]
To test the hypothesis that therapeutically induced tumor cell apoptosis might trigger an immune-suppressive response within tumor residual disease, we used an immune-competent, genetically engineered mouse model of breast cancer, MMTV-Neu [27]
On day 1, lapatinib-mediated induction of tumor cell apoptosis was seen (Fig. 1C and D). but apoptotic tumor cells (ATC) were cleared by treatment day 7, supporting use of this model to test tumor microenvironment (TME) changes occurring in response to treatment-induced tumor cell death and efferocytosis
Summary
The immune system responds to apoptotic cells (AC) in complex ways that support wound healing, suppress inflammation, limit immune-mediated tissue damage and prevent autoimmunity [1, 2]. ACs that are not dispatched lose membrane integrity and undergo secondary necrosis, releasing intracellular contents that trigger inflammation [11,12,13,14], tissue damage and in some cases, autoimmunity [5, 11, 15, 16]. MerTK loss during postpartum involution, during which, milk-producing mammary epithelial cells (MEC) undergo widespread apoptosis, impairs MEC efferocytosis, causing widespread necrosis, inflammation, and mammary scarring [17,18,19]
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