The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2

Abstract

SummaryTumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages. TRAIL-R suppression in tumor cells impaired CCL2 production and diminished both lung MDSC presence and tumor growth. In accordance, the receptor of CCL2, CCR2, is required to facilitate increased MDSC presence and tumor growth. Finally, TRAIL and CCL2 are co-regulated with MDSC/M2 markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes accumulation of tumor-supportive immune cells in the cancer microenvironment, thereby revealing a tumor-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology.

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development

“…Moreover, (4) a different complex, the PIDDosome (Tinel and Tschopp, 2004), is activated by ATM and executes apoptosis in response to DNA damage (Ando et al., 2012). Finally, (5) it was demonstrated recently that a structural (rather than enzymatic) function of these signaling complex is central for the production of chemotactic cytokines (Hartwig et al., 2017, Henry and Martin, 2017). Although not providing a direct proof of their regulatory function, the downregulation of LUBAC components and IAPs occurring in temporal association with the formation of the complex discovered here is remarkable.…”

Caspase‐8: regulating life and death

“…Because apoptotic CD95 signaling depends on FADD-caspase-8 it is assumed that it is the loss of FADD-caspase-8-induced apoptosis, permitted by RIPK3 or MLKL ablation, that is responsible for ALPS. Alternatively, since T cells from the non-cleavable caspase-8 mutant mouse do not show functional defects and splenomegaly of the mouse was not reported (71, 78), the scaffolding functions of caspase-8, important for antigen and death receptor-induced gene expression (described below) (79, 80), could be required for proper T cell functioning and simultaneously hints to a role for necroptosis in ALPS. However, whereas ripk3 D161N / D161N mice are asympomatic, co-ablation of caspase-8 induces development of ALPS in ripk3 D161N / D161N animals, suggesting that it is the balance between apoptosis and necroptosis that keeps the T cells from developing their ALPS phenotype.…”

“…The DISC rapidly forms on activated CD95 and TRAILR and initiates death, but a subsequent secondary complex, dubbed the FADDosome (80), was shown to form (Figure 4). This complex does not contain the receptor and ligand, but consists of FADD-caspase-8 in association with RIPK1, cIAP1/2, TRAF2 and NEMO, that can function to activate the NF-κB, JNK and p38 pathways (79, 80, 116, 117). The interaction between FADD and caspase-8 is integral, since TRAIL-induced cytokine expression is abrogated in cells lacking FADD or caspase-8, or cells that express a caspase-8 mutant that is unable to bind FADD (80, 117).…”

Monocyte heterogeneity and functions in cancer

“…Peripheral blood monocytes exposed to IFN‐γ or IFN‐α produce the protein TRAIL, which is able to induce cell death in TRAIL‐sensitive cancer cells . However, many cancer cells are resistant to TRAIL‐mediated apoptosis and TRAIL can instead stimulate secretion of protumoral cytokines such as CCL2 and IL‐8 . Monocytes can also induce cancer cell death through Ab‐dependent cellular cytotoxicity, which both CD14 + and CD16 + monocyte subsets have the capacity for .…”