title: Melanoma expression of matrix metalloproteinase-23 is associated with blunted tumor immunity and poor responses to immunotherapy.
abstract: BACKGROUND
  Matrix metalloproteinase-23 (MMP-23) can block the voltage-gated potassium channel Kv1.3, whose function is important for sustained Ca(2+) signaling during T cell activation. MMP-23 may also alter T cell activity and phenotype through cleavage of proteins affecting cytokine and chemokine signaling. We therefore tested the hypothesis that MMP-23 can negatively regulate the anti-tumor T cell response in human melanoma.
  
  
  METHODS
  We characterized MMP-23 expression in primary melanoma patients who received adjuvant immunotherapy. We examined the association of MMP-23 with the anti-tumor immune response - as assessed by the prevalence of tumor-infiltrating lymphocytes and Foxp3(+) regulatory T cells. Further, we examined the association between MMP-23 expression and response to immunotherapy. Considering also an in trans mechanism, we examined the association of melanoma MMP-23 and melanoma Kv1.3 expression.
  
  
  RESULTS
  Our data revealed an inverse association between primary melanoma MMP-23 expression and the anti-tumor T cell response, as demonstrated by decreased tumor-infiltrating lymphocytes (TIL) (P = 0.05), in particular brisk TILs (P = 0.04), and a trend towards an increased proportion of immunosuppressive Foxp3(+) regulatory T cells (P = 0.07). High melanoma MMP-23 expression is also associated with recurrence in patients treated with immune biologics (P = 0.037) but not in those treated with vaccines (P = 0.64). Further, high melanoma MMP-23 expression is associated with shorter periods of progression-free survival for patients receiving immune biologics (P = 0.025). On the other hand, there is no relationship between melanoma MMP-23 and melanoma Kv1.3 expression (P = 0.27).
  
  
  CONCLUSIONS
  Our data support a role for MMP-23 as a potential immunosuppressive target in melanoma, as well as a possible biomarker for informing melanoma immunotherapies.
authors.affiliation: Perlmutter Cancer Center at NYU Langone, New York, NY, USA. duane.moogk@nyumc.org.|Department of Pathology, New York University School of Medicine, New York, NY, USA. duane.moogk@nyumc.org.
authors.forename: Duane
authors.initials: D
authors.lastname: Moogk
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. ines.silva@nyumc.org.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. ines.silva@nyumc.org.|Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal. ines.silva@nyumc.org.|Programme for Advanced Medical Education, Lisbon, Portugal. ines.silva@nyumc.org.
authors.forename: Ines Pires
authors.initials: IP
authors.lastname: da Silva
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. mwm259@gmail.com.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. mwm259@gmail.com.
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Ma
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. erica.friedman@nyumc.org.|Department of Surgery, New York University School of Medicine, New York, NY, USA. erica.friedman@nyumc.org.
authors.forename: Erica B
authors.initials: EB
authors.lastname: Friedman
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. eleazar.vega-saenzdemiera@nyumc.org.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. eleazar.vega-saenzdemiera@nyumc.org.
authors.forename: Eleazar Vega-Saenz
authors.initials: EV
authors.lastname: de Miera
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA. farbod.darvishian@nyumc.org.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. farbod.darvishian@nyumc.org.
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. pjs6767@gmail.com.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. pjs6767@gmail.com.
authors.forename: Patrick
authors.initials: P
authors.lastname: Scanlon
authors.affiliation: Perlmutter Cancer Center at NYU Langone, New York, NY, USA. ennaira@gmail.com.|Department of Pathology, New York University School of Medicine, New York, NY, USA. ennaira@gmail.com.
authors.forename: Arianne
authors.initials: A
authors.lastname: Perez-Garcia
authors.affiliation: Perlmutter Cancer Center at NYU Langone, New York, NY, USA. anna.pavlick@nyumc.org.|Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. anna.pavlick@nyumc.org.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. anna.pavlick@nyumc.org.|Department of Medicine, New York University School of Medicine, New York, NY, USA. anna.pavlick@nyumc.org.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.affiliation: Perlmutter Cancer Center at NYU Langone, New York, NY, USA. nina.bhardwaj@mssm.edu.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. nina.bhardwaj@mssm.edu.|Department of Medicine, New York University School of Medicine, New York, NY, USA. nina.bhardwaj@mssm.edu.
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.affiliation: Division of Biostatistics and Epidemiology, Weill Cornell Medical College, New York, NY, USA. pac2001@med.cornell.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christos
authors.affiliation: Perlmutter Cancer Center at NYU Langone, New York, NY, USA. iman.osman@nyumc.org.|Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA. iman.osman@nyumc.org.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. iman.osman@nyumc.org.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Perlmutter Cancer Center at NYU Langone, New York, NY, USA. Michelle.Krogsgaard@nyumc.org.|Department of Pathology, New York University School of Medicine, New York, NY, USA. Michelle.Krogsgaard@nyumc.org.|Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. Michelle.Krogsgaard@nyumc.org.
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008545:Melanoma / Q000201:enzymology* / Q000276:immunology / Q000628:therapy; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D055815:Young Adult
chemical_list: C117705:MMP23B protein, human; D020782:Matrix Metalloproteinases