Oncotarget

Research Papers: Immunology:

Blocking TCR restimulation induced necroptosis in adoptively transferred T cells improves tumor control

Pravin Kesarwani, Paramita Chakraborty, Radhika Gudi, Shilpak Chatterjee, Gina Scurti, Kyle Toth, Patt Simms, Mahvash Husain, Kent Armeson, Shahid Husain, Elizabeth Garrett-Mayer, Chethamarakshan Vasu, Michael I. Nishimura and Shikhar Mehrotra _

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Oncotarget. 2016; 7:69371-69383. https://doi.org/10.18632/oncotarget.12674

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Abstract

Pravin Kesarwani1, Paramita Chakraborty1, Radhika Gudi2, Shilpak Chatterjee1, Gina Scurti3, Kyle Toth1, Patt Simms3, Mahvash Husain1, Kent Armeson4, Shahid Husain5, Elizabeth Garrett-Mayer4, Chethamarakshan Vasu2, Michael I. Nishimura3 and Shikhar Mehrotra1

1 Department of Surgery, Medical University of South Carolina, Charleston, SC, USA

2 Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA

3 Department of Surgery, Loyola University, Maywood, IL, USA

4 Department of Public Health, Medical University of South Carolina, Charleston, SC, USA

5 Department of Opthamology, Medical University of South Carolina, Charleston, SC, USA

Correspondence to:

Shikhar Mehrotra, email:

Keywords: T cell, apoptosis, melanoma, immunotherapy, Immunology and Microbiology Section, Immune response, Immunity

Received: May 12, 2016 Accepted: October 02, 2016 Published: October 14, 2016

Abstract

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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