Editorial Comment on: DPP9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer

Colorectal cancer (CRC) is a common cancer worldwide.1 In a period without effective anticancer drugs, patients with advanced CRC have a poor prognosis. However, even in advanced cases, long-term survival may be achieved by using the latest established surgical techniques, radiotherapy, and systemic chemotherapies. Chemotherapy currently includes novel cytotoxic agents, targeted molecular antibodies, and evolving immune checkpoint inhibitors (ICI).2,3,4,5,6,7 In contrast, patients with significantly advanced or recurrent CRC who do not respond to available chemotherapeutic agents do not exhibit improved outcomes. Further research is required to identify new therapeutic targets to counter therapeutic resistance in patients with CRC.

The dipeptidyl peptidase (DPP) subfamily 9b includes six members: DPP4, DPP9, DPP8, fibroblast activation protein alpha, DPP4-like protein 1, and DPP4-like protein 2.8 DPP4 is the best-known DPP family protein. It serves as a multifunctional protein involved in T cell activation and modulation of several chemokines, neuropeptides, and peptide hormones, such as neuropeptide Y, substance P, glucagon-like peptide 1, GIP, and glucagon. Several DPP4 inhibitors are currently used clinically as antidiabetic agents.9

DPP9 has attracted attention as an inflammasome repressor in human autoinflammatory diseases.10 The inflammasome is associated with cancer progression, chemosensitivity, and regulation of immune cells in the tumor microenvironment.11,12,13,14

In this issue of Annals of Surgical Oncology, Saso et al.15 focused on the significance of DPP9 expression and the potential of DPP9 targeting for chemosensitizing tumors to conventional cytotoxic agents. The authors demonstrate that the DPP9 expression levels in CRC are higher than those in noncancerous tissues and that, in patients with CRC, high DPP9 expression levels are associated with poor prognosis compared with patients with low DPP9 expression levels. Moreover, DPP9 suppression by RNA interference (RNAi) and compounds such as talabostat and vildagliptin inhibits CRC cell viability, and the combination of existing cytotoxic agents with compounds that target DPP9 increases the sensitivity of CRC cells to chemotherapy. These data suggest that DPP9 levels in CRC tissues might be a useful marker for poor prognosis and that targeting DPP9 might be useful for chemosensitizing refractory CRC.

Interestingly, the authors discussed drug repositioning of talabostat and vildagliptin, the latter already approved as a drug for diabetes treatment, for DPP9 targeting in CRC with a view toward translational research. Indeed, talabostat reportedly activates the NLRP1b inflammasome via suppression of DPP8/9, thereby inducing the antitumor immune response.16 Furthermore, vildagliptin suppresses cancer growth via regulation of NK cell activity and activation of lymphocyte chemotaxis as part of antitumor immunity.17,18 Therefore, targeting the DPP family may enhance the therapeutic effect of ICI treatment. Saso et al.15 demonstrated that high DPP9 expression in CRC was significantly associated with poor prognosis and that targeting of DPP9 by existing compounds could sensitize CRC cell lines and primary cultured CRC cells to currently used cytotoxic agents such as CPT-11 and oxaliplatin.

In the future, evaluation of DPP9 expression in pre- and posttreatment samples from CRC, including body fluid, biopsies, or resected CRC before recurrence, may be promising as a biomarker to predict the sensitivity of several key drugs such as CPT-11 and oxaliplatin as well as 5-FU and molecular targeted drugs in CRC medical care. Additional clinical studies are needed to clarify whether therapeutic strategies in combination with conventional key anticancer drugs and already-established DPP9 inhibitors show significant efficacy in patients with refractory CRC with chemoresistant characteristics. Drug repositioning of talabostat and vildagliptin for patients with CRC may promote such clinical trials more rapidly than would occur with future development of new chemicals that target DPP9.


  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6):394–424.

    Article  Google Scholar 

  2. 2.

    Brown KGM, Solomon MJ. Progress and future direction in the management of advanced colorectal cancer. Br J Surg. 2018; 105(6):615–7.

    CAS  PubMed  Google Scholar 

  3. 3.

    Ali SM, Pawlik TM, Rodriguez-Bigas MA, Monson JRT, Chang GJ, Larson DW. Timing of surgical resection for curative colorectal cancer with liver metastasis. Ann Surg Oncol. 2018; 25(1):32–7.

    PubMed  Google Scholar 

  4. 4.

    Hawkins AT, Ford MM, Geiger TM, et al. Neoadjuvant radiation for clinical T4 colon cancer: a potential improvement to overall survival. Surgery. 2019; 165(2):469–75.

    PubMed  Google Scholar 

  5. 5.

    Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol. 2015; 33(16):1787–96.

    CAS  PubMed  Google Scholar 

  6. 6.

    Siddiqui AD, Piperdi B. KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy. Ann Surg Oncol. 2010; 17(4):1168–76.

    PubMed  Google Scholar 

  7. 7.

    Boland PM, Ma WW. Immunotherapy for colorectal cancer. Cancers. 2017; 9(5):50.

    Google Scholar 

  8. 8.

    Wagner L, Klemann C, Stephan M, von Horsten S. Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins. Clin Exp Immunol. 2016; 184(3):265–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Mishriky BM, Tanenberg RJ, Sewell KA, Cummings DM. Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2018; 44(2):112–20.

    CAS  PubMed  Google Scholar 

  10. 10.

    Zhong FL, Robinson K, Teo DET, et al. Human DPP9 represses NLRP1 inflammasome and protects against autoinflammatory diseases via both peptidase activity and FIIND domain binding. J Biol Chem. 2018; 293(49):18864–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Karan D. Inflammasomes: Emerging central players in cancer immunology and immunotherapy. Front Immunol. 2018; 9:3028.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Kong H, Wang Y, Zeng X, Wang Z, Wang H, Xie W. Differential expression of inflammasomes in lung cancer cell lines and tissues. Tumour Biol. 2015; 36(10):7501–13.

    CAS  PubMed  Google Scholar 

  13. 13.

    Feng X, Luo Q, Zhang H, et al. The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma. J Exp Clin Cancer Res. 2017; 36(1):81.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    de Vasconcelos NM, Vliegen G, Goncalves A, et al. DPP8/DPP9 inhibition elicits canonical Nlrp1b inflammasome hallmarks in murine macrophages. Life Sci Alliance. 2019; 2(1):e201900313. https://doi.org/10.26508/lsa.201900313.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Saso K, Miyoshi N, Fujino S, et al. DPP9 increases chemoresistance and is an indicator of poor prognosis in colorectal cancer. Ann Surg Oncol 2020. https://doi.org/10.1245/s10434-020-08729-7.

  16. 16.

    Okondo MC, Rao SD, Taabazuing CY, Chui AJ, Poplawski SE, Johnson DC, Bachovchin DA. Inhibition of Dpp8/9 activates the Nlrp1b inflammasome. Cell Chem Biol. 2018; 25(3):262–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Jang JH, Janker F, De Meester I, et al. The CD26/DPP4-inhibitor vildagliptin suppresses lung cancer growth via macrophage-mediated NK cell activity. Carcinogenesis. 2019; 40(2):324–34.

    CAS  PubMed  Google Scholar 

  18. 18.

    Nishina S, Yamauchi A, Kawaguchi T, et al. Dipeptidyl peptidase 4 inhibitors reduce hepatocellular carcinoma by activating lymphocyte chemotaxis in mice. Cell Mol Gastroenterol Hepatol. 2019; 7(1):115–34.

    PubMed  Google Scholar 

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Correspondence to Takehiko Yokobori MD, PhD.

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Yokobori, T. Editorial Comment on: DPP9 Increases Chemoresistance and is an Indicator of Poor Prognosis in Colorectal Cancer. Ann Surg Oncol 27, 4084–4085 (2020). https://doi.org/10.1245/s10434-020-08746-6

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