Cancer Microenvironment

, Volume 11, Issue 1, pp 93–96 | Cite as

Matrix Metalloproteinase 8: Could it Benefit the CAR-T Cell Therapy of Solid Tumors?- a- Commentary on Therapeutic Potential

  • Alireza Mardomi
  • Saeid Abediankenari


Since the first experiences with genetically modified T cells in the 1980s, the concept of adoptive T cell immunotherapy has been evolved extensively [1, 2]. The introduction of chimeric antigen receptor (CAR), an artificially designed receptor on T cells against desired tumor antigens, has propelled the adoptive T cell therapy toward fair outcomes. A CAR is usually consisted up of an extracellular single chain fragment of variable (scFv) obtained from an antibody, a hinge, a transmembrane region and intracellular signaling domains [3]. This chimeric receptor provides the possibility for T cells to be activated MHC independently [4]. Therefore, can overcome the MHC down regulation and diminished antigen presentation obsereved in several malignancies [5]. The majority of CAR-T cell trials have been conducted on B cell and T cell malignancy platforms. Especially, anti-CD19 redirected CAR-T cells caused great success rate which was complete remission of 69–90% of patients...


  1. 1.
    Rosenberg SA, Eberlein TJ, Grimm EA, Lotze MT, Mazumder A, Rosenstein M (1982) Development of long-term cell lines and lymphoid clones reactive against murine and human tumors: a new approach to the adoptive immunotherapy of cancer. Surgery 92:328–336PubMedGoogle Scholar
  2. 2.
    Rosenberg SA (1984) Adoptive immunotherapy of cancer: accomplishments and prospects. Cancer Treat Rep 68:233–255PubMedGoogle Scholar
  3. 3.
    Srivastava S, Riddell SR (2015) Engineering CAR-T cells: design concepts. Trends Immunol 36:494–502CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Klebanoff CA, Rosenberg SA, Restifo NP (2016) Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22:26–36CrossRefPubMedGoogle Scholar
  5. 5.
    Han S, Latchoumanin O, Wu G, et al (2017) Recent clinical trials utilizing chimeric antigen receptor T cells therapies against solid tumors. Cancer LettGoogle Scholar
  6. 6.
    Grupp SA, Laetsch TW, Buechner J, et al (2016) Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL)Google Scholar
  7. 7.
    Maude SL, Pulsipher MA, Boyer MW, et al (2016) Efficacy and safety of CTL019 in the first US phase II multicenter trial in pediatric relapsed/refractory acute lymphoblastic leukemia: results of an interim analysisGoogle Scholar
  8. 8.
    Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507–1517CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Davila ML, Riviere I, Wang X et al (2014) Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25–224ra25CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385:517–528CrossRefPubMedGoogle Scholar
  11. 11.
    Srivastava S, Riddell SR (2018) Chimeric antigen receptor T cell therapy: challenges to bench-to-bedside efficacy. J Immunol 200:459–468CrossRefPubMedGoogle Scholar
  12. 12.
    Martínez-Cingolani C, Bories JC (2016) Development of chimeric antigen receptors for multiple myeloma. Biochem Soc Trans 44:397–405CrossRefPubMedGoogle Scholar
  13. 13.
    Tao Z, Wang M, Wang J (2016) Advances in immunotherapy of acute myeloid leukemia by using chimeric antigen receptor modified T cells. Zhonghua xue ye xue za zhi= Zhonghua xueyexue zazhi 37:160Google Scholar
  14. 14.
    Zhu Y, Tan Y, Ou R, Zhong Q, Zheng L, du Y, Zhang Q, Huang J (2016) Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. Eur J Haematol 96:389–396CrossRefPubMedGoogle Scholar
  15. 15.
    Chen KH, Wada M, Firor AE et al (2016) Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget 7:56219PubMedPubMedCentralGoogle Scholar
  16. 16.
    Turtle CJ, Riddell SR, Maloney DG (2016) CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy for B-cell malignancies. Clin Pharmacol Ther 100:252–258CrossRefPubMedGoogle Scholar
  17. 17.
    Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–461CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Garetto S, Sardi C, Morone D, Kallikourdis M (2016) Chemokines and T cell trafficking into tumors: strategies to enhance recruitment of T cells into tumors. In: Defects in T cell trafficking and resistance to Cancer immunotherapy. Springer, pp 163–177Google Scholar
  19. 19.
    Donnadieu E (2016) Defects in T cell trafficking and resistance to Cancer immunotherapy. SpringerGoogle Scholar
  20. 20.
    Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ (2008) Collagen density promotes mammary tumor initiation and progression. BMC Med 6:11CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, Friedl A, Keely PJ (2011) Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol 178:1221–1232CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A, Mami-Chouaib F, Donnadieu E (2012) Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 122:899–910CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SFT, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM (2009) Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Barcus CE, Keely PJ, Eliceiri KW, Schuler LA (2013) Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J Biol Chem 288:12722–12732CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Nishio N, Diaconu I, Liu H, et al (2014) Armed oncolytic virus enhances immune functions of chimeric antigen receptor--modified T cells in solid tumors. Cancer ResGoogle Scholar
  26. 26.
    Zheng Y, Dou Y, Duan L, Cong C, Gao A, Lai Q, Sun Y (2015) Using chemo-drugs or irradiation to break immune tolerance and facilitate immunotherapy in solid cancer. Cell Immunol 294:54–59CrossRefPubMedGoogle Scholar
  27. 27.
    Kershaw MH, Wang G, Westwood JA, Pachynski RK, Tiffany HL, Marincola FM, Wang E, Young HA, Murphy PM, Hwu P (2002) Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum Gene Ther 13:1971–1980CrossRefPubMedGoogle Scholar
  28. 28.
    Craddock JA, Lu A, Bear A, et al (2010) Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother (Hagerstown, Md 1997) 33:780Google Scholar
  29. 29.
    Di Stasi A, De Angelis B, Rooney CM et al (2009) T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113:6392–6402CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Cantor JM, Rose DM, Slepak M, Ginsberg MH (2015) Fine-tuning tumor immunity with integrin trans-regulation. Cancer Immunol Res 3:661–667CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Murphy G, Nagase H (2008) Progress in matrix metalloproteinase research. Mol Asp Med 29:290–308CrossRefGoogle Scholar
  32. 32.
    Nagase H (2001) Substrate specificity of MMPs. In: Matrix metalloproteinase inhibitors in Cancer therapy. Springer, pp 39–66Google Scholar
  33. 33.
    Shay G, Lynch CC, Fingleton B (2015) Moving targets: emerging roles for MMPs in cancer progression and metastasis. Matrix Biol 44:200–206CrossRefPubMedGoogle Scholar
  34. 34.
    Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol cell Biol 8:221–233CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Mendes O, Kim H-T, Stoica G (2005) Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin Exp Metastasis 22:237–246CrossRefPubMedGoogle Scholar
  36. 36.
    Gutiérrez-Fernández A, Fueyo A, Folgueras AR et al (2008) Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Cancer Res 68:2755–2763CrossRefPubMedGoogle Scholar
  37. 37.
    Decock J, Hendrickx W, Thirkettle S, Gutiérrez-Fernández A, Robinson SD, Edwards DR (2015) Pleiotropic functions of the tumor-and metastasis-suppressing matrix metalloproteinase-8 in mammary cancer in MMTV-PyMT transgenic mice. Breast Cancer Res 17:38CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Soria-Valles C, Gutiérrez-Fernández A, Guiu M, Mari B, Fueyo A, Gomis RR, López-Otín C (2014) The anti-metastatic activity of collagenase-2 in breast cancer cells is mediated by a signaling pathway involving decorin and miR-21. Oncogene 33:3054–3063CrossRefPubMedGoogle Scholar
  39. 39.
    Rupp LJ, Schumann K, Roybal KT, et al (2017) CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep 7:737Google Scholar
  40. 40.
    John LB, Kershaw MH, Darcy PK (2013) Blockade of PD-1 immunosuppression boosts CAR T-cell therapy. Oncoimmunology 2:e26286CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Immunogenetics Research Center, School of MedicineMazandaran University of Medical SciencesSariIran
  2. 2.Department of Immunology, School of MedicineMazandaran University of Medical SciencesSariIran

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