Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function

• Published in: Journal of immunotherapy (1997) Vol. 34; no. 3; p. 236
• Main Authors: Hernandez-Chacon, Jessica Ann, Li, Yufeng, Wu, Richard C, Bernatchez, Chantale, Wang, Yijun, Weber, Jeffrey S, Hwu, Patrick, Radvanyi, Laszlo G
• Format: Journal Article
• Language: English
• Published: United States 01.04.2011
• Subjects: Animals; Antilymphocyte Serum - pharmacology; Antilymphocyte Serum - therapeutic use; CD28 Antigens - immunology; CD28 Antigens - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Death - drug effects; Cell Death - immunology; Cell Proliferation - drug effects; Cytotoxicity, Immunologic - drug effects; Cytotoxicity, Immunologic - immunology; Humans; Immunotherapy, Adoptive - methods; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Mice; Muromonab-CD3 - pharmacology; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Receptors, OX40 - immunology; Receptors, OX40 - metabolism; Signal Transduction - drug effects; Tumor Necrosis Factor Receptor Superfamily, Member 7 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism
• ISSN: 1537-4513
• DOI: 10.1097/CJI.0b013e318209e7ec

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.