Melanoma expression of matrix metalloproteinase-23 is associated with blunted tumor immunity and poor responses to immunotherapy

Duane Moogk, Ines Pires da Silva, Michelle W. Ma, Erica B. Friedman, Eleazar Vega Saenz de Miera, Farbod Darvishian, Patrick Scanlon, Arianne Perez-Garcia, Anna C. Pavlick, Nina Bhardwaj, Paul J. Christos, Iman Osman, Michelle Krogsgaard

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Matrix metalloproteinase-23 (MMP-23) can block the voltage-gated potassium channel Kv1.3, whose function is important for sustained Ca2+ 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.

Original languageEnglish
Article number342
JournalJournal of Translational Medicine
Volume12
Issue number1
DOIs
StatePublished - 10 Dec 2014
Externally publishedYes

Keywords

  • Immunotherapy
  • Kv1.3
  • Matrix metalloproteinase-23
  • Melanoma
  • Tumor-infiltrating lymphocytes

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