Abstract
Hepatocellular carcinoma (HCC) is generally considered an "immune-cold" cancer since T cells are not observed abundantly in HCC tumor tissue. Combination therapy with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors is currently recognized as a first-line systemic treatment for advanced-stage HCC. Immunologically, immune checkpoint inhibitors influence the recognition of cancer cells by T cells, and VEGF inhibitors influence the infiltration of T cells into tumors. However, no drugs that facilitate the trafficking of T cells toward tumors have been developed. Chemokines are promising agents that activate T cell trafficking. On the other hand, metabolic factors such as obesity and insulin resistance are considered risk factors for HCC development. CD26/dipeptidyl peptidase 4 (DPP4) functions as a serine protease, selectively cleaving polypeptides with a proline or alanine at the penultimate N-terminal position, such as chemokines. Recently, CD26/DPP4 has been reported to attenuate anticancer immunity via chemokine cleavage and to promote insulin resistance and inflammation in the liver and/or adipose tissue via dysregulation of macrophage M1/M2 polarization. In this review, we discuss the promotive roles of CD26/DPP4 in HCC development and progression and the potential of DPP4 inhibitors as therapeutic agents for HCC.
Highlights
Introduction iationsHepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide
HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), a major hepatic manifestation of the metabolic disorder [24]. These results suggest that the increased expression of CD26/dipeptidyl peptidase 4 (DPP4) in HCC may be linked to obesity in some patients
In addition to the role of DPP4 as an adipokine with the potential to induce insulin resistance, DPP4 expressed on dendric cells/macrophages play a critical role in potentiating inflammation of adipose tissue in obesity [76]
Summary
Recent progress in the treatment of advanced HCC has shed light on anti-tumor immunity. In agreement with these results, a recent report showed that ARI-4175, a pan inhibitor of the DPP4 enzyme family, enhanced CD8+ T cell recruitment and activated intrahepatic inflammasome in a murine model of HCC [46] Consistent with these results in biochemical experiments and animal models, two prospective clinical trials in healthy donors and in chronic hepatitis C patients revealed that DPP4 inhibitor (sitagliptin) treatment resulted in a significant decrease in the truncated CXCL10 (3–77) concentration and a reciprocal increase in CXCL10 (1–77), with only minimal effects on the total levels of the chemokine [47]. Multivariate analysis identified circMET exprestrimethylation (H3K27me3) [54] This type of chemokine induction is totally sion as an independent predictor of poor overall survival and high postoperative +recurdifferent from that induced by DPP4 inhibitors, 2-DG-PLGA-NPs enhance CD8 T cell rence in 209 HCC patients [33]. These results suggest that the effects of DPP4 inhibitors on the metastasis of cancer cells may be dependent on cancer cell type or experimental model
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