Tumor-Derived Extracellular Vesicles Impair CD171-Specific CD4+ CAR T Cell Efficacy

Chimeric antigen receptor (CAR) T cell efficacy against solid tumors is currently limited by several immune escape mechanisms, which may include tumor-derived extracellular vesicles. Advanced neuroblastoma is an aggressive childhood tumor without curative treatment options for most relapsed patients today. We here evaluated the role of tumor-derived extracellular vesicles on the efficacy of CAR T cells targeting the neuroblastoma-specific antigen, CD171. For this purpose, CAR T cell activation, cytokine production, exhaustion, and tumor cell-directed cytotoxicity upon co-culture was evaluated. Tumor-derived extracellular vesicles isolated from SH-SY5Y neuroblastoma cells neither affected CAR T cell activation nor expression of inhibitory markers. Importantly, exposure of CD4+ CD171-specific CAR T cells to tumor-derived extracellular vesicles significantly impaired tumor cytotoxicity of CAR T cells. This effect was independent of neurotrophic receptor tyrosine kinases 1 or 2 (NTRK1, NTRK2) expression, which is known to impact immune responses against neuroblastoma. Our results demonstrate for the first time the impact of tumor-derived extracellular vesicles and non-cell-mediated tumor-suppressive effects on CD4+ CAR T cell efficacy in a preclinical setting. We conclude that these factors should be considered for any CAR T cell-based therapy to make CAR T cell therapy successful against solid tumors

Multiphoton absorption in amyloid protein fibres

Fibrillization of peptides leads to the formation of amyloid fibres, which, when in large aggregates, are responsible for diseases such as Alzheimer's and Parkinson's. Here, we show that amyloids have strong nonlinear optical absorption, which is not present in native non-fibrillized protein. Z-scan and pump-probe experiments indicate that insulin and lysozyme β-amyloids, as well as α-synuclein fibres, exhibit either two-photon, three-photon or higher multiphoton absorption processes, depending on the wavelength of light. We propose that the enhanced multiphoton absorption is due to a cooperative mechanism involving through-space dipolar coupling between excited states of aromatic amino acids densely packed in the fibrous structures. This finding will provide the opportunity to develop nonlinear optical techniques to detect and study amyloid structures and also suggests that new protein-based materials with sizable multiphoton absorption could be designed for specific applications in nanotechnology, photonics and optoelectronics

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the prometastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy

Syntheses of Pentanuclear Group 6 Iridium Clusters by Core Expansion of Tetranuclear Clusters with Ir(CO)2(η5-C5Me4R) (R = H, Me)

Mixed molybdenum/tungsten tetrairidium and dimolybdenum/ditungsten triiridium clusters were prepared in high yield by cluster-core expansion of molybdenum/tungsten triiridium and dimolybdenum/ditungsten diiridium precursors, respectively, and were analyzed by a combination of spectroscopic, structural, and theoretical techniques. Tetrahedral molybdenum/tungsten iridium mixed-metal clusters undergo cluster-core expansion with iridium capping reagents to afford trigonal-bipyramidal MIr4(μ-CO)3(CO)7(η5-C5H5)(η5-L′), MoIr4(μ3-H)(μ-CO)2(μ-η1:η5-CH2C5Me4)(CO)7(η5-C5Me5) (possessing a μ-η1:η5-CH2C5Me4 ligand derived from a C−H bond activation of a C5Me5 methyl group), M2Ir3(μ-CO)3(CO)6(η5-C5H5)2(η5-L′), W2Ir3(μ-CO)4(CO)5(η5-C5H5)2(η5-C5Me4H), and Mo2Ir3(μ-CO)3(CO)6(η5-C5Me5)2 (L′ = C5Me5, C5Me4H). The spectroscopic, electrochemical, and spectroelectrochemical behavior of the clusters have been rationalized by time-dependent density functional theory