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.
Highlights
Recent advancements in adoptive cell therapy (ACT) have led to the use of T cells engineered with tumor specific T cell receptors for targeting tumor growth [1]
While our previous data shows that tumor epitope reactive T cells undergo caspaseindependent cell death that involves reactive oxygen species (ROS) and jun N terminal kinase (JNK) [14, 15], we further evaluated the morphological changes associated with TCR restimulation cell death in CD62Llo T cells (Figure 1A)
The CD62Llo fraction that was stimulated with control peptide, exhibited less cell death indicating that induction of necroptosis is due to antigen specific TCR restimulation
Summary
Recent advancements in adoptive cell therapy (ACT) have led to the use of T cells engineered with tumor specific T cell receptors for targeting tumor growth [1]. Recent studies have shown that necrosis may occur in a “programmed” manner just like apoptosis, and this form of necrotic death is known as “necroptosis” [4, 5]. This form of cell death shares characteristics of both necrosis and apoptosis. The multiplicity of cell death pathways and relevant proteins provides additional opportunities to develop new strategies for therapeutic inhibition of cell death
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