Costimulation Through the CD137/4-1BB Pathway Protects Human Melanoma Tumor-infiltrating Lymphocytes From Activation-induced Cell Death and Enhances Antitumor Effector Function
- 1 April 2011
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of Immunotherapy
- Vol. 34 (3), 236-250
- https://doi.org/10.1097/cji.0b013e318209e7ec
Abstract
Adoptive T-cell therapy (ACT) using expanded tumor-infiltrating lymphocytes (TIL) with high-dose interleukin-2 is a promising form of immunotherapy for stage IV melanoma having clinical response rates of 50% or more. One of the major problems preventing further success of this therapy is that the current protocols used to highly expand TIL for infusion drive CD8+ T cells to differentiate into effector cells losing key costimulatory molecules such as CD28 and CD27. This has been associated with a lack of persistence in vivo for reasons not entirely clear. In this study, we demonstrate that while human melanoma CD8+ TIL lost CD27 and CD28 expression during the rapid expansion for ACT, they gained expression of the alternative costimulatory molecule CD137/4-1BB, and to a lesser extent CD134/OX40. Postrapid expansion protocol (REP) TIL were found to be highly sensitive to activation-induced cell death when reactivated through the T-cell receptor with low levels of OKT3 antibody. However, coligation of 4-1BB using 2 different agonistic anti-4-1BB antibodies potently prevented activation-induced cell death of post-REP CD8+ TIL, including those specific for melanoma antigen recognized by T cells, and facilitated even further cell expansion. This was correlated with increased levels of bcl-2 and bcl-xL together with decreased bim expression. 4-1BB costimulated post-REP TIL also expressed increased levels of the cytolytic granule proteins and exhibited enhanced cytotoxic T-cell activity against melanoma cells. Lastly, post-REP CD8+ TIL were protected from cell death by anti-4-1BB ligation when exposed to human leukocyte antigen-matched melanoma cells. Our results indicate that 4-1BB costimulation may significantly improve TIL survival during melanoma ACT and boost antitumor cytolytic activity.Keywords
This publication has 41 references indexed in Scilit:
- Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412New England Journal of Medicine, 2006
- Modulation by IL-2 of CD70 and CD27 Expression on CD8+ T Cells: Importance for the Therapeutic Effectiveness of Cell Transfer ImmunotherapyThe Journal of Immunology, 2006
- Telomere Length of Transferred Lymphocytes Correlates with In Vivo Persistence and Tumor Regression in Melanoma Patients Receiving Cell Transfer TherapyPublished by The American Association of Immunologists ,2005
- Neuroblastoma Cells Transiently Transfected to Simultaneously Express the Co-Stimulatory Molecules CD54, CD80, CD86, and CD137L Generate Antitumor Immunity in MiceJournal of Immunotherapy, 2005
- A sensitive flow cytometry-based cytotoxic T-lymphocyte assay through detection of cleaved caspase 3 in target cellsJournal of Immunological Methods, 2005
- Survival, Persistence, and Progressive Differentiation of Adoptively Transferred Tumor-Reactive T Cells Associated with Tumor RegressionJournal of Immunotherapy, 2005
- TNF/TNFR FAMILY MEMBERS IN COSTIMULATION OF T CELL RESPONSESAnnual Review of Immunology, 2005
- Cutting Edge: Persistence of Transferred Lymphocyte Clonotypes Correlates with Cancer Regression in Patients Receiving Cell Transfer TherapyPublished by The American Association of Immunologists ,2004
- 4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell ResponsesThe Journal of Experimental Medicine, 1997
- Costimulation of CD28- T lymphocytes by 4-1BB ligand.The Journal of Immunology, 1997