Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity

Maarten A. Ligtenberg, Dimitrios Mougiakakos, Madhura Mukhopadhyay, Kristina Witt, Alvaro Lladser, Markus Chmielewski, Tobias Riet, Hinrich Abken, Rolf Kiessling

Resultado de la investigación: Contribución a una revistaArtículo

48 Citas (Scopus)

Resumen

Treatment of cancer patients by adoptive T cell therapy has yielded promising results. In solid tumors, however, T cells encounter a hostile environment, in particular with increased inflammatory activity as a hallmark of the tumor milieu that goes along with abundant reactive oxygen species (ROS) that substantially impair antitumor activity. We present a strategy to render antitumor T cells more resilient toward ROS by coexpressing catalase along with a tumor specific chimeric Ag receptor (CAR) to increase their antioxidative capacity by metabolizing H2O2. In fact, T cells engineered with a bicistronic vector that concurrently expresses catalase, along with the CAR coexpressing catalase (CAR-CAT), performed superior over CAR T cells as they showed increased levels of intracellular catalase and had a reduced oxidative state with less ROS accumulation in both the basal state and upon activation while maintaining their antitumor activity despite high H2O2 levels. Moreover, CAR-CAT T cells exerted a substantial bystander protection of nontransfected immune effector cells as measured by CD3ζ chain expression in bystander T cells even in the presence of high H2O2 concentrations. Bystander NK cells, otherwise ROS sensitive, efficiently eliminate their K562 target cells under H2O2-induced oxidative stress when admixed with CAR-CAT T cells. This approach represents a novel means for protecting tumor-infiltrating cells from tumor-associated oxidative stress-mediated repression.

Idioma originalInglés
Páginas (desde-hasta)759-766
Número de páginas8
PublicaciónJournal of Immunology
Volumen196
N.º2
DOI
EstadoPublicada - 15 ene 2016

Áreas temáticas de ASJC Scopus

  • Inmulogía y alergología
  • Inmunología

Huella Profundice en los temas de investigación de 'Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity'. En conjunto forman una huella única.

  • Citar esto

    Ligtenberg, M. A., Mougiakakos, D., Mukhopadhyay, M., Witt, K., Lladser, A., Chmielewski, M., Riet, T., Abken, H., & Kiessling, R. (2016). Coexpressed catalase protects chimeric antigen receptor-redirected T cells as well as bystander cells from oxidative stress-induced loss of antitumor activity. Journal of Immunology, 196(2), 759-766. https://doi.org/10.4049/jimmunol.1401710