Hartwig, Torsten; (2018) Molecular and functional determinants of the TRAIL-induced tumour-supportive secretome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing a wide range of cancer cells in vivo, without toxicity to non-transformed cells. The initial enthusiasm about the therapeutic potential of TRAIL was however dampened in recent years, as it has become apparent that many human primary tumour cells are resistant to TRAIL-mediated apoptosis. In certain resistant cells, TRAIL-mediated non-apoptotic signals can even promote tumour progression migration and invasion which, as recently demonstrated by our laboratory, can involve cancer-cell autonomous mechanisms mediated by the endogenous TRAIL/TRAIL-R system independently of FADD. Interestingly, TRAIL has recently also been shown to induce the secretion of cytokines. Cytokines have been characterized as central orchestrators of the tumour microenvironment and can modulate its composition to either promote or inhibit tumour growth. However, it was not known whether and to which extent TRAIL/TRAIL-R signalling in cancer cells can affect the immune-microenvironment. Based on these findings, the aim of this dissertation was to study the role of the TRAIL-induced secretome in tumour biology. This thesis demonstrates that TRAIL-induced cytokine production from TRAIL-resistant cancer cells is FADD-dependent, and identifies the TRAIL-induced secretome to drive monocyte polarisation to M2-like myeloid derived suppressor cells (MDSC) and tumour-associated macrophages (TAM), two alternatively activated myeloid cell subsets. Strikingly, TRAIL-R suppression in tumour cells impaired CCL2 production and diminished both, MDSC accumulation in lungs of tumour-bearing mice and tumour growth. In accordance, the receptor of CCL2, CCR2, was required to facilitate increased MDSC recruitment and tumour growth. Finally, TRAIL and CCL2 are co-expressed with M2-like markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes the accumulation of alternatively activated myeloid cells in the cancer microenvironment, in favour of tumour growth. Hence, this dissertation reveals a novel tumour-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology.

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