CD26/DPP4 - a potential biomarker and target for cancer therapy

Our plain-English summary of CD26/DPP4 - a potential biomarker and target for cancer therapy, by N. Enz, G. Vliegen, I. De Meester, et al (Pharmacology & Therapeutics, 2019).

The study

• Authors: N. Enz, G. Vliegen, I. De Meester, W. Jungraithmayr
• Journal: Pharmacology & Therapeutics
• Published: 2019;198:135-159
• Type of article: Review
• Cited by: 134 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

CD26/dipeptidyl peptidase (DPP)4 is a membrane-bound protein found in many cell types of the body, and a soluble form is present in body fluids. There is longstanding evidence that various primary tumors and also metastases express CD26/DPP4 to a variable extent. By cleaving dipeptides from peptides with a proline or alanine in the penultimate position at the N-terminus, it regulates the activity of incretin hormones, chemokines and many other peptides. Due to these effects and interactions with other molecules, a tumor promoting or suppressing role can be attributed to CD26/DPP4. In this review, we discuss the existing evidence on the expression of soluble or membrane-bound CD26/DPP4 in malignant diseases, along with the most recent findings on CD26/DPP4 as a therapeutic target in specific malignancies. The expression and possible involvement of the related DPP8 and DPP9 in cancer are also reviewed. A higher expression of CD26/DPP4 is found in a wide variety of tumor entities, however more research on CD26/DPP4 in the tumor microenvironment is needed to fully explore its use as a tumor biomarker. Circulating soluble CD26/DPP4 has also been studied as a cancer biomarker, however, the observed decrease in most cancer patients does not seem to be cancer specific. Encouraging results from experimental work and a recently reported first phase clinical trial targeting CD26/DPP4 in mesothelioma, renal and urological tumors pave the way for follow-up clinical studies, also in other tumor entities, possibly leading to the development of more effective complementary therapies against cancer.

Copyright © 2019 Elsevier Inc. All rights reserved.

In plain English

This was a review of published research on CD26/DPP4 in many cancers, including malignant pleural mesothelioma. CD26/DPP4 is a cell-surface protein also found in soluble form in body fluids. DPP8 and DPP9 were also reviewed. The article did not study asbestos exposure. Asbestos appeared only in one reviewed blood study comparing 80 mesothelioma patients with 79 patients with past asbestos exposure and pleural plaques. It reported lower serum CD26 levels and enzyme activity in mesothelioma patients. Other cited studies found CD26 in most epithelioid and biphasic mesotheliomas but not sarcomatoid ones; one found cytoplasmic CD26 in all. The authors reported only one phase I trial targeting CD26/DPP4 in human cancer: the antibody YS110, given to patients with CD26-expressing tumors resistant or refractory to standard therapy. It found the antibody well tolerated, with disease stabilized in mesothelioma patients. The authors noted that low blood CD26 also occurs outside cancer and that many studies were small or used only healthy controls. They concluded that CD26/DPP4 holds promise as part of a biomarker panel but needs more study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research on CD26/DPP4 (and the related enzymes DPP8 and DPP9) in cancer
• Who was studied: No study population of its own. The authors reviewed published laboratory, animal and clinical studies of CD26/DPP4 in many cancer types, including malignant pleural mesothelioma.
• Exposure: Not an asbestos exposure study. Asbestos appears only as the comparison group in one reviewed blood study of mesothelioma (Fujimoto et al., 2014): 79 patients with past asbestos exposure and pleural plaques.
• Main results:
  • Cited study (Inamoto et al., 2007): in seven tissue samples from mesothelioma patients, CD26 was highly expressed in malignant mesothelioma cells but not in benign mesothelial cells.
  • Cited study (Aoe et al., 2012), 79 mesothelioma patients: CD26 was expressed in the majority of epithelioid and biphasic types but was lacking in the sarcomatoid type.
  • Cited study (Amatya et al., 2011): cytoplasmic CD26 was found in all histological subtypes of mesothelioma.
  • Cited study (Aoe et al., 2012): CD26 expression did not correlate with survival time, but was associated with a better prognosis in mesothelioma patients given non-pemetrexed chemotherapy regimens.
  • Cited study (Fujimoto et al., 2014), 80 malignant pleural mesothelioma patients compared with 79 patients with past asbestos exposure and pleural plaques: serum soluble CD26 levels and enzyme activity were lower in the mesothelioma patients.
  • Cited study (Fujimoto et al., 2014): mesothelioma patients with higher serum DPP4 enzyme activity had longer median overall survival than those with lower activity.
  • The authors stated that, for CD26/DPP4 as a therapeutic target in human cancer, there was currently only one phase I clinical trial (Angevin et al., 2017). The review separately describes earlier phase II trials of talabostat, a pan-inhibitor of the DPP enzymes.
  • That phase I trial gave the anti-CD26 antibody YS110 to patients with CD26-expressing tumors (mesothelioma, renal cell and urothelial carcinoma) that were resistant or refractory to standard therapy.
  • In that phase I trial, the antibody was well tolerated and stabilized disease in the mesothelioma patients.
  • The authors noted that a decrease in blood soluble CD26/DPP4 is not limited to cancer.
• The authors' conclusion: The authors concluded that CD26/DPP4 holds promise as part of a panel of biomarkers in cancer and in the treatment of some cancer types. They added that its role is complex and that more experimental and clinical studies are needed.
• Limitations the authors state:
  • The authors stated that several patient groups in the reviewed blood-biomarker studies were small.
  • The authors stated that many reviewed studies used only healthy people as controls, not patients with other non-cancer diseases.
  • The authors stated that in most reviewed studies, enzyme activity assays were not confirmed to measure DPP4 specifically, so related enzymes may have contributed.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Cleaving, Tumor Microenvironment, Clinical Trial, Mesothelioma.

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