Targeting lL-38 triggers γδ T cell-dependent anti-tumor immunity

Abstract The IL-1 family receptor antagonist IL-38 suppresses auto-inflammatory reactions in murine disease models. Given the connection between auto-immunity and anti-tumor immunity, we wondered if targeting would affect latter. transgenic PyMT mammary carcinoma model was employed to target genetically or with a neutralizing antibody. IL-38-deficient (KO) mice had markedly delayed tumor growth compared WT mice, accompanied by increased NK cells, CD8+, NKT, γδ T cell infiltrates. Accordingly, human carcinoma, expression negatively correlated infiltrating subsets. This pattern largely recapitulated IL-38-neutralizing antibody, where antibody-treated showed strong decrease IgG control treated animals, an increase CD8+ cells. In therapeutic of chemoresistance, antibody combination doxorubicin prevented relapse, which CD4+, To analyze involvement used γδ-TCR blocking KO mice. delay tumors abolished upon blockade. cells effective blockade, suggesting cross talking Whole transcriptome sequencing analysis neutralization blockage suggested NOTCH signaling mediate link Taken together, these results provide evidence for potential anti-IL-38 antibodies activate immunity carcinoma. Supported grant from Deutsche Krebshilfe (70114051)