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


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 postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti-CD137 mAb thus results from in vivo enhancement and sustainment of effector functions.

SUBMITTER: Weigelin B 

PROVIDER: S-EPMC4475992 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Weigelin Bettina B   Bolaños Elixabet E   Teijeira Alvaro A   Martinez-Forero Ivan I   Labiano Sara S   Labiano Sara S   Azpilikueta Arantza A   Morales-Kastresana Aizea A   Quetglas José I JI   Wagena Esther E   Sánchez-Paulete Alfonso Rodríguez AR   Chen Lieping L   Friedl Peter P   Melero Ignacio I  

Proceedings of the National Academy of Sciences of the United States of America 20150601 24


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  ...[more]

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