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
Department of Cell Biology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, The Netherlands;
Centro de Investigación Médica Aplicada (CIMA) and Clinica Universidad de Navarra, University of Navarra, 31008 Pamplona, Spain;
Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7551-6. doi: 10.1073/pnas.1506357112. Epub 2015 Jun 1.
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.
由于近期通过优化的过继性T细胞转移和免疫刺激性单克隆抗体（mAb）在临床取得的成功，癌症免疫疗法正在取得重大进展。源自B16F10的表达OVA的小鼠黑色素瘤对用活化的抗OVA OT1 CTL过继性转移或激动剂抗CD137（4-1BB）mAb进行的根治性免疫疗法具有抗性。然而，当联合使用时，这些治疗方法始终能实现肿瘤根除。实现肿瘤排斥的肿瘤浸润淋巴细胞在转移的OT-1和内源性细胞毒性T淋巴细胞（CTL）中均表现出增强的效应器功能。这与转移的和内源性CTL中更高水平的胚外中胚层决定因子表达一致，也与活体活细胞双光子显微镜观察到的更有效的CTL介导的肿瘤细胞杀伤证据一致。抗CD137 mAb治疗导致OT1 CTL效应细胞在肿瘤内的持续时间延长，并通过OT-1 CTL与靶细胞的聚焦和局限相互作用动力学改善了功能，增加了凋亡诱导，持续到过继性转移后六天。因此，过继性T细胞疗法和激动剂抗CD137 mAb的协同作用源于效应器功能在体内的增强和维持。
