Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb
Weigelin B(1), Bolaños E(2), Teijeira A(2), Martinez-Forero I(2), Labiano S(2), Azpilikueta A(2), Morales-Kastresana A(2), Quetglas JI(2), Wagena E(1), Sánchez-Paulete AR(2), Chen L(3), Friedl P(1), Melero I(4).
(1) Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;
(2) Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
(3) Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06511;
(4) Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain.
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.
CITATION Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7551-6. doi: 10.1073/pnas.1506357112.