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2016 ; 7
(43
): 69371-69383
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gab.com Text
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Blocking TCR restimulation induced necroptosis in adoptively transferred T cells
improves tumor control
#MMPMID27750220
Kesarwani P
; Chakraborty P
; Gudi R
; Chatterjee S
; Scurti G
; Toth K
; Simms P
; Husain M
; Armeson K
; Husain S
; Garrett-Mayer E
; Vasu C
; Nishimura MI
; Mehrotra S
Oncotarget
2016[Oct]; 7
(43
): 69371-69383
PMID27750220
show ga
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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