Lecomte, E. | Search bioRxiv

bioRxiv2026

Interferon-γ promotes SMAP production by cytotoxic T lymphocytes in a thrombospondin 4 dependent manner

Cytotoxic T lymphocytes (CTLs) eliminate infected and cancerous cells by exocytosing cytotoxic granules, either as single-core granules (SCGs) releasing diffusible Granzyme B and Perforin, or as multi-core granules (MCGs) releasing these effectors as thrombospondin-1/4-encapsulated supramolecular attack particles (SMAPs). How CTLs differentially deploy these granule types remains unclear. We demonstrate that prolonged in vitro expansion and restimulation selectively enhance SMAP release, correlating with increased MCG maturation and thrombospondin-4 expression. Using high-resolution imaging, we identify fusion-competent MCG intermediates lacking SMAPs but releasing granzyme B diffusively. Mechanistically, interferon-{gamma} upregulates thrombospondin-4, driving MCG maturation and SMAP biogenesis, enhancing late-phase CTL killing efficiency against resistant targets. Consistent with this, THBS1 and THBS4 transcript levels appear elevated in melanoma-infiltrating CTLs compared with those during acute adenovirus infection. These findings define a stimulus-dependent, interferon-{gamma}-driven pathway tailoring CTL responses to chronic pathology and highlight opportunities for SMAP-targeted immunotherapies.

immunology↗

bioRxiv2023

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Neuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of tumor-driving events. Here, we identify a novel tumor-suppressor gene that predicts poor survival in high-risk disease, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss of MOXD1 leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and mice in vivo models. One-Sentence SummaryNeural crest-specific MOXD1 is a de novo tumor-suppressor gene in childhood cancers arising during embryogenesis.

cancer biology↗