Abstract
Inhibition of DPP4 promotes an IL33-driven eosinophil-mediated antitumor response.
Major finding: Inhibition of DPP4 promotes an IL33-driven eosinophil-mediated antitumor response.
Mechanism: DPP4 inhibition promotes migration of eosinophils into tumors by preventing inactivation of CCL11.
Impact: Combination therapy of DPP4i and immune checkpoint blockade may have therapeutic potential.
Post-translational modifications of chemokines can have significant effects on their functions. Dipeptidyl peptidase 4 (DPP4), also known as CD26, cleaves proteins at an amino acid consensus motif that is found on 18 different human chemokines, among them CXCL10. Previous studies have shown that cleavage of CXCL10 by DPP4 reduces migration of T cells and natural killer cells in several tumor models. Additionally, treatment with the DPP4 inhibitor (DPP4i) sitagliptin increases lymphocyte trafficking to tumors and improves tumor immunity and response to T cell–mediated therapy in mouse models. Hollande and colleagues further investigated the mechanism by which inhibition of DPP4 reduces tumor growth in syngeneic and orthotopic models of hepatocellular carcinoma (HCC) and breast cancer and found that eosinophils migrate to the tumor site to facilitate the DPP4i-mediated antitumor effect. Furthermore, profiling cytokine and chemokine expression in DPP4i-treated tumor extracts revealed higher expression of the eosinophil chemoattractant CCL11, which is a known target for DPP4-mediated truncation and inactivation, and the cytokine IL33, known to have a role in activation of eosinophil effector function. Neutralization of CCL11 eliminated the antitumor effect of DPP4i, whereas injection of CCL11 promoted eosinophil migration. In addition, expression of IL33 by tumor cells was a prerequisite for the antitumor effect of eosinophils, with blockade of IL33 resulting in reduced efficacy of DPP4i in in vivo models and forced IL33 expression conferring sensitivity to eosinophil targeting that did not previously exist. These findings demonstrate that the CCL11–IL33 axis is crucial for the DPP4i antitumor response mediated by eosinophils. Combined treatment with sitagliptin and anti–PD-1 and anti-CTLA4 also resulted in a significant reduction of tumor growth, indicating that T cells and eosinophils interact in mediating DPP4i antitumor response. Collectively, these results elucidate a mechanism by which eosinophils contribute to intrinsic antitumor immunity and checkpoint inhibitor–induced antitumor immunity. The combination of DPP4 inhibition and immune checkpoint blockade may therefore have therapeutic potential for patients with cancer.
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