XIAP promotes melanoma growth by inducing tumour neutrophil infiltration
Mila Daoud, Pia Nora Broxtermann, Fabian Schorn, J Paul Werthenbach, Jens M. Seeger, Lars M. Schiffmann, Kerstin Brinkmann, Domagoj Vucic, Thomas Tüting, Cornelia Mauch, Dagmar Kulms, Paola Zigrino, Hamid Kashkar
Abstract
Elevated expression of the X‐linked inhibitor of apoptosis protein (XIAP) has been frequently reported in malignant melanoma suggesting that XIAP renders apoptosis resistance and thereby supports melanoma progression. Independent of its anti‐apoptotic function, XIAP mediates cellular inflammatory signalling and promotes immunity against bacterial infection. The pro‐inflammatory function of XIAP has not yet been considered in cancer. By providing detailed in vitro analyses, utilising two independent mouse melanoma models and including human melanoma samples, we show here that XIAP is an important mediator of melanoma neutrophil infiltration. Neutrophils represent a major driver of melanoma progression and are increasingly considered as a valuable therapeutic target in solid cancer. Our data reveal that XIAP ubiquitylates RIPK2, involve TAB1/RIPK2 complex and induce the transcriptional up‐regulation and secretion of chemokines such as IL8, that are responsible for intra‐tumour neutrophil accumulation. Alteration of the XIAP‐RIPK2‐TAB1 inflammatory axis or the depletion of neutrophils in mice reduced melanoma growth. Our data shed new light on how XIAP contributes to tumour growth and provides important insights for novel XIAP targeting strategies in cancer. XIAP controls melanoma growth without interfering with apoptotic signalling. XIAP induces RIPK2‐mediated inflammatory signalling which provokes neutrophil infiltration and supports tumour progression. XIAP controls melanoma growth without interfering with apoptotic signalling. XIAP induces RIPK2‐mediated inflammatory signalling which provokes neutrophil infiltration and supports tumour progression.