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7 pages, 257 KiB

Open AccessEditorial

CD26 and Cancer

by Oscar J. Cordero

Cancers 2022, 14(21), 5194; https://doi.org/10.3390/cancers14215194 - 23 Oct 2022

Cited by 4 | Viewed by 1590

Abstract

This Special Issue presents new knowledge on the complex behaviour of dipeptidyl peptidase 4 (DPP4, EC 3 [...] Full article

(This article belongs to the Special Issue CD26 and Cancer)

Research

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14 pages, 705 KiB

Open AccessArticle

Evaluation of Blood Soluble CD26 as a Complementary Biomarker for Colorectal Cancer Screening Programs

by Loretta De Chiara, Leticia Barcia-Castro, María Gallardo-Gómez, María Páez de la Cadena, Vicenta S. Martínez-Zorzano, Francisco J. Rodríguez-Berrocal, Luis Bujanda, Ane Etxart, Antoni Castells, Francesc Balaguer, Rodrigo Jover, Joaquín Cubiella and Oscar J. Cordero

Cancers 2022, 14(19), 4563; https://doi.org/10.3390/cancers14194563 - 20 Sep 2022

Cited by 3 | Viewed by 1506

Abstract

Fecal hemoglobin immunodetection (FIT) in combination with endoscopy has been implemented to reduce mortality from colorectal cancer (CRC), although there are issues that can be improved in relation to participation rates. We studied whether the blood biomarker soluble-CD26 (sCD26), related at least in [...] Read more.

Fecal hemoglobin immunodetection (FIT) in combination with endoscopy has been implemented to reduce mortality from colorectal cancer (CRC), although there are issues that can be improved in relation to participation rates. We studied whether the blood biomarker soluble-CD26 (sCD26), related at least in part to the immune system and inflammation, and/or its dipeptidyl peptidase enzyme activity (DPP4), could help reduce false positives. In a cohort of 1703 individuals who underwent colonoscopy and had a serum sample, sCD26 and DPP4 activity showed statistically significant differences regarding sex and age. According to the colonoscopy findings, sCD26 and DPP4 activity progressively decreased in advanced adenomas and CRC, with statistically significant differences, even between both groups; 918 of them had a FIT result (n = 596 positive cases) with approximately 70% of these (n = 412) false positives. With cut-offs of 440 ng/mL for sCD26, 42 mU/mL for DPP4, and 11 ng/mU for their ratio, the combined information of the three biomarkers (at least positive for one biomarker) identified almost all advanced adenomas and CRC cases in the FIT cohort with approximately half of the false positives compared to FIT. A sequential testing strategy with FIT and our blood biomarker test is proposed. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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21 pages, 8349 KiB

Open AccessArticle

Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

by James M. Henderson, Michelle S. W. Xiang, Jiali Carrie Huang, Stefanie Wetzel, Linxuan Jiang, Jack H. Lai, Wengen Wu, James G. Kench, William W. Bachovchin, Ben Roediger, Geoffrey W. McCaughan, Hui Emma Zhang and Mark D. Gorrell

Cancers 2021, 13(21), 5495; https://doi.org/10.3390/cancers13215495 - 1 Nov 2021

Cited by 17 | Viewed by 3500

Abstract

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour [...] Read more.

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8⁺ T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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13 pages, 2078 KiB

Open AccessArticle

Repurposing DPP-4 Inhibitors for Colorectal Cancer: A Retrospective and Single Center Study

by Lui Ng, Dominic Chi-Chung Foo, Carlos King-Ho Wong, Abraham Tak-Ka Man, Oswens Siu-Hung Lo and Wai-Lun Law

Cancers 2021, 13(14), 3588; https://doi.org/10.3390/cancers13143588 - 17 Jul 2021

Cited by 16 | Viewed by 4246

Abstract

Background: There have been studies reporting the crucial roles of Dipeptidyl-peptidase 4 (DPP4) in colorectal cancer (CRC) initiation and progression, whereas DPP4-inhibitors are safe Food and Drug Association (FDA)-approved drugs for treating diabetes. This study aims to investigate the association between DPP4-inhibitor treatment [...] Read more.

Background: There have been studies reporting the crucial roles of Dipeptidyl-peptidase 4 (DPP4) in colorectal cancer (CRC) initiation and progression, whereas DPP4-inhibitors are safe Food and Drug Association (FDA)-approved drugs for treating diabetes. This study aims to investigate the association between DPP4-inhibitor treatment and the prognosis of CRC patients. Methods: Clinical data of CRC patients with diabetes and the prescription of DPP4-inhibitors who had undergone curative surgery in our hospital between January 2006 and December 2015 were retrieved. Their survival data and immune cell population in circulatory blood were compared to those treated with metformin. Results: The DPP4-inhibitor patient group showed a significantly better 5-year disease-free survival (median DFS = 1733 days, 95% CI = 1596 to 1870 days) when compared to the metformin group (p = 0.030, median DFS = 1382 days, 95% CI = 1246 to 1518 days). 33 out of the 92 patients in the metformin group showed recurrence whereas only 3 of the 26 patients in the DPP4-inhibitor group showed recurrence (p = 0.033). Cox regression analysis demonstrated that DPP4-inhibitor application is a favorable factor associated with a lower risk of recurrence (Hazard ratio = 0.200, p = 0.035). Furthermore, our results suggested that the immune cell profile of CRC patients is a potential biomarker for response to DPP4-inhibitor treatment. Conclusion: This study demonstrated the association of DPP4-inhibitor treatment with a better prognosis of CRC patients. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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18 pages, 4199 KiB

Open AccessArticle

DPP4 Inhibitor Sitagliptin Enhances Lymphocyte Recruitment and Prolongs Survival in a Syngeneic Ovarian Cancer Mouse Model

by Amy L. Wilson, Laura R. Moffitt, Kirsty L. Wilson, Maree Bilandzic, Mark D. Wright, Mark D. Gorrell, Martin K. Oehler, Magdalena Plebanski and Andrew N. Stephens

Cancers 2021, 13(3), 487; https://doi.org/10.3390/cancers13030487 - 27 Jan 2021

Cited by 19 | Viewed by 4262

Abstract

Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to [...] Read more.

Immunity plays a key role in epithelial ovarian cancer (EOC) progression with a well-documented correlation between patient survival and high intratumoral CD8+ to T regulatory cell (Treg) ratios. We previously identified dysregulated DPP4 activity in EOCs as a potentially immune-disruptive influence contributing to a reduction in CXCR3-mediated T-cell infiltration in solid tumours. We therefore hypothesized that inhibition of DPP4 activity by sitagliptin, an FDA-approved inhibitor, would improve T-cell infiltration and function in a syngeneic ID8 mouse model of EOC. Daily oral sitagliptin at 50 mg/kg was provided to mice with established primary EOCs. Sitagliptin treatment decreased metastatic tumour burden and significantly increased overall survival and was associated with significant changes to the immune landscape. Sitagliptin increased overall CXCR3-mediated CD8+ T-cell trafficking to the tumour and enhanced the activation and proliferation of CD8+ T-cells in tumour tissue and the peritoneal cavity. Substantial reductions in suppressive cytokines, including CCL2, CCL17, CCL22 and IL-10, were also noted and were associated with reduced CD4+ CD25+ Foxp3+ Treg recruitment in the tumour. Combination therapy with paclitaxel, however, typical of standard-of-care for patients in palliative care, abolished CXCR3-specific T-cell recruitment stimulated by sitagliptin. Our data suggest that sitagliptin may be suitable as an adjunct therapy for patients between chemotherapy cycles as a novel approach to enhance immunity, optimise T-cell-mediated function and improve overall survival. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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Review

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28 pages, 950 KiB

Open AccessReview

Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease?

by Petr Busek, Jonathan S. Duke-Cohan and Aleksi Sedo

Cancers 2022, 14(9), 2072; https://doi.org/10.3390/cancers14092072 - 21 Apr 2022

Cited by 22 | Viewed by 3715

Abstract

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis [...] Read more.

Dipeptidyl peptidase IV (DPP-IV, CD26) is frequently dysregulated in cancer and plays an important role in regulating multiple bioactive peptides with the potential to influence cancer progression and the recruitment of immune cells. Therefore, it represents a potential contributing factor to cancer pathogenesis and an attractive therapeutic target. Specific DPP-IV inhibitors (gliptins) are currently used in patients with type 2 diabetes mellitus to promote insulin secretion by prolonging the activity of the incretins glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Nevertheless, the modulation of the bioavailability and function of other DPP-IV substrates, including chemokines, raises the possibility that the use of these orally administered drugs with favorable side-effect profiles might be extended beyond the treatment of hyperglycemia. In this review, we critically examine the possible utilization of DPP-IV inhibition in cancer prevention and various aspects of cancer treatment and discuss the potential perils associated with the inhibition of DPP-IV in cancer. The current literature is summarized regarding the possible chemopreventive and cytotoxic effects of gliptins and their potential utility in modulating the anti-tumor immune response, enhancing hematopoietic stem cell transplantation, preventing acute graft-versus-host disease, and alleviating the side-effects of conventional anti-tumor treatments. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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11 pages, 716 KiB

Open AccessReview

CD26/DPP-4 in Chronic Myeloid Leukemia

by Anna Sicuranza, Donatella Raspadori and Monica Bocchia

Cancers 2022, 14(4), 891; https://doi.org/10.3390/cancers14040891 - 11 Feb 2022

Cited by 7 | Viewed by 2675

Abstract

CD26 expression is altered in many solid tumors and hematological malignancies. Recently, it has been demonstrated that it is a specific marker expressed on LSCs of CML, both in BM and PB samples, and absent on CD34+/CD38− stem cells in normal subjects or [...] Read more.

CD26 expression is altered in many solid tumors and hematological malignancies. Recently, it has been demonstrated that it is a specific marker expressed on LSCs of CML, both in BM and PB samples, and absent on CD34+/CD38− stem cells in normal subjects or on LSCs of other myeloid neoplasms. CD26+ LSCs have been detected by flow-cytometry assays in all PB samples of Chronic-Phase CML patients evaluated at diagnosis. Additionally, it has been demonstrated that most CML patients undergoing Tyrosine Kinase Inhibitors (TKIs) treatment still harbored circulating measurable residual CD26+ LSCs, even when displaying a consistent deep molecular response without any significant association among the amounts of BCR-ABL transcript and CD26+ LSCs. Preliminary data of our Italian prospective multicenter study showed that CML patients with a poorer response presented with a higher number of CD26+ LSCs at diagnosis. These data confirmed that CD26 is a specific marker of CML and suggest that it could be considered for the monitoring of therapeutic responses. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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15 pages, 1349 KiB

Open AccessReview

CD26/DPP4 as a Therapeutic Target in Nonalcoholic Steatohepatitis Associated Hepatocellular Carcinoma

by Sohji Nishina and Keisuke Hino

Cancers 2022, 14(2), 454; https://doi.org/10.3390/cancers14020454 - 17 Jan 2022

Cited by 12 | Viewed by 5093

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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18 pages, 1666 KiB

Open AccessReview

The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells

by Guranda Chitadze, Ulrike Wehkamp, Ottmar Janssen, Monika Brüggemann and Marcus Lettau

Cancers 2021, 13(23), 5947; https://doi.org/10.3390/cancers13235947 - 26 Nov 2021

Cited by 13 | Viewed by 3845

Abstract

CD26/Dipeptidylpeptidase 4 is a transmembrane serine protease that cleaves off N-terminal dipeptides. CD26/DPP4 is expressed on several immune cell types including T and NK cells, dendritic cells, and activated B cells. A catalytically active soluble form of CD26/DPP4 can be released from the [...] Read more.

CD26/Dipeptidylpeptidase 4 is a transmembrane serine protease that cleaves off N-terminal dipeptides. CD26/DPP4 is expressed on several immune cell types including T and NK cells, dendritic cells, and activated B cells. A catalytically active soluble form of CD26/DPP4 can be released from the plasma membrane. Given its wide array of substrates and interaction partners CD26/DPP4 has been implicated in numerous biological processes and effects can be dependent or independent of its enzymatic activity and are exerted by the transmembrane protein and/or the soluble form. CD26/DPP4 has been implicated in the modulation of T-cell activation and proliferation and CD26/DPP4-positive T cells are characterized by remarkable anti-tumor properties rendering them interesting candidates for T cell-based immunotherapies. Moreover, especially in cutaneous T-cell lymphoma CD26/DPP4 expression patterns emerged as an established marker for diagnosis and treatment monitoring. Surprisingly, besides a profound knowledge on substrates, interaction partners, and associated signal transduction pathways, the precise role of CD26/DPP4 for T cell-based immune responses is only partially understood. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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36 pages, 1296 KiB

Open AccessReview

The Role of Post-Translational Modifications of Chemokines by CD26 in Cancer

by Alexandra De Zutter, Jo Van Damme and Sofie Struyf

Cancers 2021, 13(17), 4247; https://doi.org/10.3390/cancers13174247 - 24 Aug 2021

Cited by 12 | Viewed by 3262

Abstract

Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity [...] Read more.

Chemokines are a large family of small chemotactic cytokines that fulfill a central function in cancer. Both tumor-promoting and -impeding roles have been ascribed to chemokines, which they exert in a direct or indirect manner. An important post-translational modification that regulates chemokine activity is the NH₂-terminal truncation by peptidases. CD26 is a dipeptidyl peptidase (DPPIV), which typically clips a NH₂-terminal dipeptide from the chemokine. With a certain degree of selectivity in terms of chemokine substrate, CD26 only recognizes chemokines with a penultimate proline or alanine. Chemokines can be protected against CD26 recognition by specific amino acid residues within the chemokine structure, by oligomerization or by binding to cellular glycosaminoglycans (GAGs). Upon truncation, the binding affinity for receptors and GAGs is altered, which influences chemokine function. The consequences of CD26-mediated clipping vary, as unchanged, enhanced, and reduced activities are reported. In tumors, CD26 most likely has the most profound effect on CXCL12 and the interferon (IFN)-inducible CXCR3 ligands, which are converted into receptor antagonists upon truncation. Depending on the tumor type, expression of CD26 is upregulated or downregulated and often results in the preferential generation of the chemokine isoform most favorable for tumor progression. Considering the tight relationship between chemokine sequence and chemokine binding specificity, molecules with the appropriate characteristics can be chemically engineered to provide innovative therapeutic strategies in a cancer setting. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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18 pages, 767 KiB

Open AccessEditor’s ChoiceReview

CD26/DPP-4: Type 2 Diabetes Drug Target with Potential Influence on Cancer Biology

by Emi Kawakita, Daisuke Koya and Keizo Kanasaki

Cancers 2021, 13(9), 2191; https://doi.org/10.3390/cancers13092191 - 2 May 2021

Cited by 23 | Viewed by 6326

Abstract

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as [...] Read more.

DPP-4/CD26, a membrane-bound glycoprotein, is ubiquitously expressed and has diverse biological functions. Because of its enzymatic action, such as the degradation of incretin hormones, DPP-4/CD26 is recognized as the significant therapeutic target for type 2 diabetes (T2DM); DPP-4 inhibitors have been used as an anti-diabetic agent for a decade. The safety profile of DPP-4 inhibitors for a cardiovascular event in T2DM patients has been widely analyzed; however, a clear association between DPP-4 inhibitors and tumor biology is not yet established. Previous preclinical studies reported that DPP-4 suppression would impact tumor progression processes. With regard to this finding, we have shown that the DPP-4 inhibitor induces breast cancer metastasis and chemoresistance via an increase in its substrate C-X-C motif chemokine 12, and the consequent induction of epithelial-mesenchymal transition in the tumor. DPP-4/CD26 plays diverse pivotal roles beyond blood glucose control; thus, DPP-4 inhibitors can potentially impact cancer-bearing T2DM patients either favorably or unfavorably. In this review, we primarily focus on the possible undesirable effect of DPP-4 inhibition on tumor biology. Clinicians should note that the safety of DPP-4 inhibitors for diabetic patients with an existing cancer is an unresolved issue, and further mechanistic analysis is essential in this field. Full article

(This article belongs to the Special Issue CD26 and Cancer)

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