Cancer cells co-opt an inter-organ neuroimmune circuit to escape immune surveillance
Menée à l'aide de trois modèles murins de cancer de la cavité buccale et à l'aide de données cliniques portant sur des patients atteints d'un carcinome épidermoïde de la tête et du cou, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses, via notamment l'activation des neurones nociceptifs innervant la tumeur, favorise la croissance tumorale et réduit l'efficacité des inhibiteurs de point de contrôle immunitaire
Whether and how cancer exploits distant organs to escape immune surveillance remains largely unknown. Using clinical data from head and neck squamous cell carcinoma (HNSCC) patients and three murine oral cancer models, we find that cancer cells under immune pressure secrete slit guidance ligand 2 (SLIT2) through an activating transription factor 4 (ATF4)-dependent pathway, which activates tumor-innervating nociceptive neurons and aggravates cancer-induced pain. This activation then stimulates tumor-draining lymph-node (TDLN)-innervating nociceptive neurons and increases calcitonin gene-related peptide (CGRP) secretion, remodeling TDLNs into an immune-suppressed state. Consequently, decreased CCL5 secretion from immune-suppressed TDLNs promotes M2-like polarization of tumor-associated macrophages, facilitating tumor growth and reducing immune checkpoint blockade (ICB) efficacy. Targeting nociceptive neurons or the ATF4-SLIT2-CGRP axis restores immune activity, alleviates cancer-induced pain, and improves ICB responses. Our findings reveal an inter-organ neuroimmune circuit co-opted by cancer to escape immune surveillance, suggesting potential therapeutic strategies to enhance immunotherapy.
Cell , résumé, 2025