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

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Cytotoxic T-Lymphocytes
Adoptive Transfer
Immunotherapy
Neoplasms
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Cell- and Tissue-Based Therapy
Photons
Microscopy
Melanoma
Apoptosis
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Weigelin, B., Bolaños, E., Teijeira, A., Martinez-Forero, I., Labiano, S., Azpilikueta, A., ... Melero, I. (2015). Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. Proceedings of the National Academy of Sciences of the United States of America, 112(24), 7551-7556. https://doi.org/10.1073/pnas.1506357112

Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. / Weigelin, Bettina; Bolaños, Elixabet; Teijeira, Alvaro; Martinez-Forero, Ivan; Labiano, Sara; Azpilikueta, Arantza; Morales-Kastresana, Aizea; Quetglas, José I.; Wagena, Esther; Sánchez-Paulete, Alfonso Rodríguez; Chen, Lieping; Friedl, Peter; Melero, Ignacio.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 24, 16.06.2015, p. 7551-7556.

Research output: Contribution to journalArticle

Weigelin, B, Bolaños, E, Teijeira, A, Martinez-Forero, I, Labiano, S, Azpilikueta, A, Morales-Kastresana, A, Quetglas, JI, Wagena, E, Sánchez-Paulete, AR, Chen, L, Friedl, P & Melero, I 2015, 'Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 24, pp. 7551-7556. https://doi.org/10.1073/pnas.1506357112
Weigelin, Bettina ; Bolaños, Elixabet ; Teijeira, Alvaro ; Martinez-Forero, Ivan ; Labiano, Sara ; Azpilikueta, Arantza ; Morales-Kastresana, Aizea ; Quetglas, José I. ; Wagena, Esther ; Sánchez-Paulete, Alfonso Rodríguez ; Chen, Lieping ; Friedl, Peter ; Melero, Ignacio. / Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 24. pp. 7551-7556.
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