XIAP promotes melanoma growth by inducing tumour neutrophil infiltration

X-linked inhibitor of apoptosis (XIAP) is a member of the inhibitors of apoptosis proteins (IAPs) and it negatively regulates apoptosis via direct interaction and inhibition of caspase activity. XIAP expression is highly increased in malignant melanoma, thus XIAP was considered to mediate apoptosis resistance and therefore promotes melanoma progression. In addition to XIAP anti-apoptotic function, XIAP is involved in inflammatory responses and can induce NFκB activation. However, the inflammatory function of XIAP is still not considered in cancer. Our data show that XIAP supports melanoma tumour growth independently of its anti-apoptotic function. Moreover, XIAP mediates chemokine secretion like IL8, which mediates neutrophil chemo-attraction. Furthermore, our data reveal that XIAP forms a signalling complex with RIPK2 and TAB1. The XIAP-RIPK2-TAB1 complex mediates chemokine secretion and intra-tumoural neutrophil infiltration. Finally, deficiency of XIAP-RIPK2-TAB1 complex or depletion of neutrophils reduced melanoma growth in mice. Collectively, our data revealed a major signalling pathway that mediates melanoma growth and thus, identifies XIAP as a novel therapeutic target in cancer by targeting its inflammatory function

Incommensurate magnetism in the coupled spin tetrahedra system Cu2Te2O5Cl2

Neutron scattering studies on powder and single crystals have provided new evidences for unconventional magnetism in Cu2Te2O5Cl2. The compound is built from tetrahedral clusters of S=1/2 Cu2+ spins located on a tetragonal lattice. Magnetic ordering, emerging at TN=18.2 K, leads to a very complex multi-domain, most likely degenerate, ground state, which is characterized by an incommensurate (ICM) wave vector k ~ [0.15, 0.42,1/2]. The Cu2+ ions carry a magnetic moment of 0.67(1) mB/ Cu2+ at 1.5 K and form a four helices spin arrangement with two canted pairs within the tetrahedra. A domain redistribution is observed when a magnetic field is applied in the tetragonal plane (Hc≈0.5 T), but not for H||c up to 4 T. The excitation spectrum is characterized by two well-defined modes, one completely dispersionless at 6.0 meV, the other strongly dispersing to a gap of 2 meV. The reason for such complex ground state and spin excitations may be geometrical frustration of the Cu2+ spins within the tetrahedra, intra- and inter-tetrahedral couplings having similar strengths and strong Dzyaloshinski-Moriya anisotropy. Candidates for the dominant intra- and inter-tetrahedral interactions are proposed

XIAP promotes melanoma growth by inducing tumour neutrophil infiltration

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

Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma

Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8(+) T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8(+) T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4(R24C )(Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8(+) T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4(R24C), promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4(R24C) antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies