Suppression of CD26 inhibits growth and metastasis of pancreatic cancer

Ye, Chunxiang; Tian, Xiuyun; Yue, Guanjun; Liang, Yan; Guan, Xiaoya; Wang, Shan; Hao, Chunyi

doi:10.1007/s13277-016-5315-4

Cited by 10 publications

(7 citation statements)

References 25 publications

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“…Despite previous reports that DPP4 knockdown reduces human PDAC cell line proliferation in vitro, 26 we found that BXCL701 had no effect on mT3-2D proliferation or viability in vitro (online supplemental figure 1B-D). To test BXCL701's impact on PDAC tumor growth in vivo, we injected C57BL/6 mice subcutaneously with 1×10 5 mT3-2D cells, waited for the tumors to reach 40-50 mm 3 , then began BXCL701 treatment.…”

Section: Dpp Inhibitor Bxcl701 Reduces Mt3-2d Tumor Growth and Prolongs Overall Survivalcontrasting

confidence: 99%

DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

Fitzgerald

Wang

Agarwal³

et al. 2021

J Immunother Cancer

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer death in the USA by 2030. Immune checkpoint inhibitors fail to control most PDAC tumors because of PDAC’s extensive immunosuppressive microenvironment and poor immune infiltration, a phenotype also seen in other non-inflamed (ie, ‘cold’) tumors. Identifying novel ways to enhance immunotherapy efficacy in PDAC is critical. Dipeptidyl peptidase (DPP) inhibition can enhance immunotherapy efficacy in other cancer types; however, the impact of DPP inhibition on PDAC tumors remains unexplored.MethodsWe examined the effects of an oral small molecule DPP inhibitor (BXCL701) on PDAC tumor growth using mT3-2D and Pan02 subcutaneous syngeneic murine models in C57BL/6 mice. We explored the effects of DPP inhibition on the tumor immune landscape using RNAseq, immunohistochemistry, cytokine evaluation and flow cytometry. We then tested if BXCL701 enhanced anti-programmed cell death protein 1 (anti-PD1) efficacy and performed immune cell depletion and rechallenged studies to explore the relevance of cytotoxic immune cells to combination treatment efficacy.ResultsIn both murine models of PDAC, DPP inhibition enhanced NK and T cell immune infiltration and reduced tumor growth. DPP inhibition also enhanced the efficacy of anti-PD1. The efficacy of dual anti-PD1 and BXCL701 therapy was dependent on both CD8+ T cells and NK cells. Mice treated with this combination therapy developed antitumor immune memory that cleared some tumors after re-exposure. Lastly, we used The Cancer Genome Atlas (TCGA) to demonstrate that increased NK cell content, but not T cell content, in human PDAC tumors is correlated with longer overall survival. We propose that broad DPP inhibition enhances antitumor immune response via two mechanisms: (1) DPP4 inhibition increases tumor content of CXCL9/10, which recruits CXCR3+ NK and T cells, and (2) DPP8/9 inhibition activates the inflammasome, resulting in proinflammatory cytokine release and Th1 response, further enhancing the CXCL9/10-CXCR3 axis.ConclusionsThese findings show that DPP inhibition with BXCL701 represents a pharmacologic strategy to increase the tumor microenvironment immune cell content to improve anti-PD1 efficacy in PDAC, suggesting BXCL701 can enhance immunotherapy efficacy in ‘cold’ tumor types. These findings also highlight the potential importance of NK cells along with T cells in regulating PDAC tumor growth.

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Section: Dpp Inhibitor Bxcl701 Reduces Mt3-2d Tumor Growth and Prolongs Overall Survivalcontrasting

confidence: 99%

DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

Fitzgerald

Wang

Agarwal³

et al. 2021

J Immunother Cancer

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“…Our results indicated that CD26 was aberrantly expressed in pancreatic tumors and may be involved in pancreatic tumorigenesis as an oncogene, which corroborates the findings of our previous study. 9 Similarly to our results, CD26 was overexpressed in patients with thyroid cancer, 7 , 14 malignant mesothelioma, 15 ovarian carcinoma, 16 and HCC. 17 Particularly, in patients with HCC, CD26 overexpression was correlated with the proliferation marker ki-67 in tumor cells, thereby indicating that CD26 expression may be involved in tumorigenic proliferation.…”

Section: Discussionsupporting

confidence: 88%

“… 8 Our previous work showed that CD26 overexpression promotes the growth and invasion of pancreatic cancer cells, whereas suppression of CD26 inhibits malignant behaviors. 9 However, CD26 expression in specimens from patients with pancreatic tumors has not been extensively investigated.…”

Section: Introductionmentioning

confidence: 99%

<p>CD26 as a Promising Biomarker for Predicting Prognosis in Patients with Pancreatic Tumors</p>

Liang¹,

Tian²,

Ye³

et al. 2020

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Purpose Pancreatic cancer is associated with a high mortality rate owing to insufficient approaches for early diagnosis and the invasive biological behavior of the cancer. CD26 is a membrane-anchored protein involved in multiple physiological and pathological processes. Here, we investigated correlations between CD26 expression and clinicopathological features in patients with pancreatic tumors. Methods We collected 170 tumor tissue specimens and 138 paired paratumoral tissues from patients with pancreatic tumors and evaluated CD26 expression using immunohistochemistry. Results CD26 was expressed in 79.4% of pancreatic tumors, which was significantly ( P < 0.001) higher than that in paratumoral pancreatic tissues (23.2%). High expression of CD26 was correlated with ABO blood type ( P = 0.035), malignancy degree ( P = 0.001), CA199 ( P = 0.01), and CA242 ( P = 0.027). In pancreatic malignancies, CD26 expression was observed in 80.7% (130/161) of cases. Lower CD26 expression was correlated with longer disease-free survival ( P = 0.048) and overall survival ( P = 0.024) and was an independent predictor of overall survival (hazard ratio [HR]: 1.713; P = 0.042). Similar results were observed in pancreatic ductal adenocarcinoma (PDAC) tissues, and CD26 expression level (HR: 2.117; P = 0.008) was an independent predictor of overall survival in patients with PDAC. CD26 expression was significantly increased in pancreatic tumors and gradually increased with increasing malignancy degree, suggesting that CD26 may be involved in the tumorigenic proliferation of pancreatic tumors. Conclusion Therefore, CD26 is a potential marker for early diagnosis and a promising therapeutic target in pancreatic tumors.

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“…It has been previously shown that suppression of CD26 expression inhibited metastasis of pancreatic cancer 29 . Moreover, the flavonoid apigenin restrained metastasis of lung cancer by downregulation of CD26 30 .…”

Section: Introductionmentioning

confidence: 96%

The mechanism of sitagliptin inhibition of colorectal cancer cell lines' metastatic functionalities

et al. 2021

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The cell membrane glycoprotein CD26 with peptidase activity (DPP4) and/or its soluble CD26/DPP4 counterpart expression and/or activity are altered in several cancers. Its role in metastasis development was recently highlighted by the discovery of CD26+ cancer stem cell subsets and the fact that clinical DPP4 inhibitors showed antimetastatic effects in animal models. Also, diabetic patients treated with the DPP4 inhibitor sitagliptin showed greater overall survival after colorectal or lung cancer surgery than patients under other diabetic therapies. However, the mechanism of action of these inhibitors in this context is unclear. We studied the role of CD26 and its DPP4 enzymatic activity in malignant cell features such as cell‐to‐cell homotypic aggregation, cancer cell motility, and invasion in a panel of human colorectal cancer (CRC) cell lines, avoiding models that include the physiological role of DPP4 in chemotaxis. Present results indicate that CD26 participates in the induction of cell invasion, motility, and aggregation of CD26‐positive CRC cell lines. Moreover, only invasion and motility assays, which are collagen matrix‐dependent, showed a decrease upon treatment with the DPP4 inhibitor sitagliptin. Sitagliptin showed opposite effects to those of transforming growth factor‐β1 on epithelial‐to‐mesenchymal transition and cell cycle, but this result does not explain its CD26/DPP4‐dependent effect. These results contribute to the elucidation of the molecular mechanisms behind sitagliptin inhibition of metastatic traits. At the same time, this role of sitagliptin may help to define areas of medicine where DPP4 inhibitors might be introduced. However, they also suggest that additional tools against CD26 as a target might be used or developed for metastasis prevention in addition to gliptins.

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Suppression of CD26 inhibits growth and metastasis of pancreatic cancer

Cited by 10 publications

References 25 publications

DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

DPP inhibition alters the CXCR3 axis and enhances NK and CD8+ T cell infiltration to improve anti-PD1 efficacy in murine models of pancreatic ductal adenocarcinoma

<p>CD26 as a Promising Biomarker for Predicting Prognosis in Patients with Pancreatic Tumors</p>

The mechanism of sitagliptin inhibition of colorectal cancer cell lines' metastatic functionalities

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