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

Abstract

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