Browsing by Author "Crawford, Jeremy Chase"

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    Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1–Dependent Myeloid Cells
    (American Association for Cancer Research, 2021) Van de Velde, Lee-Ann; Allen, E. Kaitlynn; Crawford, Jeremy Chase; Wilson, Taylor L.; Guy, Clifford S.; Russier, Marion; Zeitler, Leonie; Bahrami, Armita; Finkelstein, David; Pelletier, Stephane; Schultz-Cherry, Stacey; Thomas, Paul G.; Murray, Peter J.; Medicine, School of Medicine
    Immune cells regulate tumor growth by mirroring their function as tissue repair organizers in normal tissues. To understand the different facets of immune-tumor collaboration through genetics, spatial transcriptomics, and immunologic manipulation with noninvasive, longitudinal imaging, we generated a penetrant double oncogene-driven autochthonous model of neuroblastoma. Spatial transcriptomic analysis showed that CD4+ and myeloid populations colocalized within the tumor parenchyma, while CD8+ T cells and B cells were peripherally dispersed. Depletion of CD4+ T cells or CCR2+ macrophages, but not B cells, CD8+ T cells, or natural killer (NK) cells, prevented tumor formation. Tumor CD4+ T cells displayed unconventional phenotypes and were clonotypically diverse and antigen independent. Within the myeloid fraction, tumor growth required myeloid cells expressing arginase-1. Overall, these results demonstrate how arginine-metabolizing myeloid cells conspire with pathogenic CD4+ T cells to create permissive conditions for tumor formation, suggesting that these protumorigenic pathways could be disabled by targeting myeloid arginine metabolism. SIGNIFICANCE: A new model of human neuroblastoma provides ways to track tumor formation and expansion in living animals, allowing identification of CD4+ T-cell and macrophage functions required for oncogenesis.
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    The interaction between RIPK1 and FADD controls perinatal lethality and inflammation
    (Elsevier, 2024) Rodriguez, Diego A.; Tummers, Bart; Shaw, Jeremy J. P.; Quarato, Giovanni; Weinlich, Ricardo; Cripps, James; Fitzgerald, Patrick; Janke, Laura J.; Pelletier, Stephane; Crawford, Jeremy Chase; Green, Douglas R.; Medical and Molecular Genetics, School of Medicine
    Perturbation of the apoptosis and necroptosis pathways critically influences embryogenesis. Receptor-associated protein kinase-1 (RIPK1) interacts with Fas-associated via death domain (FADD)-caspase-8-cellular Flice-like inhibitory protein long (cFLIPL) to regulate both extrinsic apoptosis and necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality. This lethality is not prevented by further removal of the kinase activity of Ripk1 (Ripk1R588E K45A [REKA]). Both Ripk1RE and Ripk1REKA animals survive to adulthood upon ablation of Ripk3. While embryonic lethality of Ripk1RE mice is prevented by ablation of the necroptosis effector mixed lineage kinase-like (MLKL), animals succumb to inflammation after birth. In contrast, Mlkl ablation does not prevent the death of Ripk1REKA embryos, but animals reach adulthood when both MLKL and caspase-8 are removed. Ablation of the nucleic acid sensor Zbp1 largely prevents lethality in both Ripk1RE and Ripk1REKA embryos. Thus, the RIPK1-FADD interaction prevents Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated embryonic lethality, affected by the kinase activity of RIPK1.