Journal Article
. 2011 Mar; 34(3):236-50.
doi: 10.1097/CJI.0b013e318209e7ec.

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

Jessica Ann Hernandez-Chacon 1 Yufeng Li  Richard C Wu  Chantale Bernatchez  Yijun Wang  Jeffrey S Weber  Patrick Hwu  Laszlo G Radvanyi  
Affiliations
  • PMID: 21389874
  •     41 References
  •     63 citations

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.

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Eur J Immunol, 2020 Nov 13; 51(3). PMID: 33180337    Free PMC article.
Multifaceted modes of action of the anticancer probiotic Enterococcus hirae.
Anne-Gaëlle Goubet, Richard Wheeler, +27 authors, Romain Daillère.
Cell Death Differ, 2021 May 13; 28(7). PMID: 33976389    Free PMC article.
Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment.
Racheal Louise Johnson, Michele Cummings, +3 authors, Nicolas Michel Orsi.
Cancers (Basel), 2021 Dec 25; 13(24). PMID: 34944851    Free PMC article.
Review.
Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies.
Javier Glez-Vaz, Arantza Azpilikueta, +13 authors, Ignacio Melero.
J Immunother Cancer, 2022 Mar 04; 10(3). PMID: 35236742    Free PMC article.