Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb

Bettina Weigelin, Elixabet Bolaños, Alvaro Teijeira, Ivan Martinez-Forero, Sara Labiano, Arantza Azpilikueta, Aizea Morales-Kastresana, José I. Quetglas, Esther Wagena, Alfonso Rodríguez Sánchez-Paulete, Lieping Chen, Peter Friedl, Ignacio Melero

Research output: Contribution to journalArticle

Abstract

Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days post-adoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.

Original languageEnglish (US)
Pages (from-to)7551-7556
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number24
DOIs
StatePublished - Jun 16 2015
Externally publishedYes

Keywords

  • Adoptive T-cell therapy
  • CD137
  • Costimulation
  • Cytotoxic T lymphocyte
  • Immunotherapy

ASJC Scopus subject areas

  • General

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