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Blocking TCR restimulation induced necroptosis in adoptively transferred T cells improves tumor control.
Kesarwani, Pravin; Chakraborty, Paramita; Gudi, Radhika; Chatterjee, Shilpak; Scurti, Gina; Toth, Kyle; Simms, Patt; Husain, Mahvash; Armeson, Kent; Husain, Shahid; Garrett-Mayer, Elizabeth; Vasu, Chethamarakshan; Nishimura, Michael I; Mehrotra, Shikhar.
Afiliación
  • Kesarwani P; Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
  • Chakraborty P; Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
  • Gudi R; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
  • Chatterjee S; Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
  • Scurti G; Department of Surgery, Loyola University, Maywood, IL, USA.
  • Toth K; Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
  • Simms P; Department of Surgery, Loyola University, Maywood, IL, USA.
  • Husain M; Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
  • Armeson K; Department of Public Health, Medical University of South Carolina, Charleston, SC, USA.
  • Husain S; Department of Opthamology, Medical University of South Carolina, Charleston, SC, USA.
  • Garrett-Mayer E; Department of Public Health, Medical University of South Carolina, Charleston, SC, USA.
  • Vasu C; Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
  • Nishimura MI; Department of Surgery, Loyola University, Maywood, IL, USA.
  • Mehrotra S; Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
Oncotarget ; 7(43): 69371-69383, 2016 Oct 25.
Article en En | MEDLINE | ID: mdl-27750220
Advancements in adoptive cell transfer therapy (ACT) has led to the use of T cells engineered with tumor specific T cell receptors, which after rapid expansion can be obtained in sufficient numbers for treating patients. However, due to massive proliferation these cells are close to replicative senescence, exhibit exhausted phenotype, and also display increased susceptibility to activation induced cell death. We have previously shown that tumor reactive T cells undergo caspase-independent cell death upon TCR restimulation with cognate antigen, which involves reactive oxygen species and c-jun N-terminal kinase. Herein, we show that a large fraction of the human melanoma epitope tyrosinase reactive TCR transduced T cells that exhibit effector memory (TEM) phenotype and undergo programmed necrosis, or necroptosis, upon TCR restimulation. As compared to the T central memory (TCM) subsets, the TEM subset displayed an increased expression of genes involved in necroptotic cell death, and a necrotic phenotype upon TCR restimulation as confirmed by electron microscopy. Higher expression of receptor-interacting kinases (RIPK) that mediate necroptosis was also observed in the TEM fraction. Further, the TEM cells were rescued from undergoing necroptosis when pretreated with necroptotic inhibitor NecroX2 before TCR restimulation. Importantly, NecroX2 pretreated tumor reactive T cells also exhibited better tumor control and increased in vivo persistence when adoptively-transferred to treat subcutaneously established murine melanoma B16-F10. Thus, it is likely that the outcome of ACT could be vastly improved by interfering with the necroptotic cell death pathway in activated tumor reactive T cells used in immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Melanoma Experimental / Receptores de Antígenos de Linfocitos T / Inmunoterapia Adoptiva / Apoptosis / Linfocitos T CD8-positivos Límite: Animals / Humans Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Melanoma Experimental / Receptores de Antígenos de Linfocitos T / Inmunoterapia Adoptiva / Apoptosis / Linfocitos T CD8-positivos Límite: Animals / Humans Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos