Efficacy of Adoptive T-cell Therapy Is Improved by Treatment with the Antioxidant N-Acetyl Cysteine, Which Limits Activation-Induced T-cell Death

Abstract

While adoptive transfer of autologous tumor antigen-specific T cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53. Activation of this DNA damage response pathway also occurred upon antigen-specific restimulation in TCR-transduced TIL1383I T cells prepared for adoptive transfer to patients as part of a clinical trial. Notably, treatment with the antioxidant N-acetyl cysteine (NAC) significantly reduced upregulation of the DNA damage marker γH2AX, subsequent ATM activation and cell death. In the Pmel mouse model of melanoma, the presence of NAC during ex vivo T cell expansion improved the persistence of adoptively transferred cells, reduced tumor growth and increased survival. Taken together, our results offer a preclinical proof of concept for the addition of NAC to current therapeutic T cell expansion protocols, offering immediate potential to improve the quality and therapeutic efficacy of adoptive T cell therapeutics infused into patients.

High-throughput single-cell live imaging of photobiomodulation with multispectral near-infrared lasers in cultured T cells

“…Recent study has shown that central memory T cells with higher cytosolic glutathione, surface thiol, and intracellular antioxidant levels survive longer in tumor and control tumor growth than effector memory T cells with less antioxidant levels and that treatment with antioxidants improved the function of tumor-infiltrating T lymphocytes (TILs), leading to prolonged survival of patients receiving these treated TIL. 102 Further work is warranted to determine if this system could be broadly used to discover such a combination parameter of NIR lasers.…”

Endoplasmic Reticulum Protein Disulfide Isomerase Shapes T Cell Efficacy for Adoptive Cellular Therapy of Tumors

“…Based on enhanced oxidative stress, our data indicate that excessive PDI-ERO1α activity may undermine glutathione homeostasis in effector T cells. These data are important in the context of cancer immunotherapy, because maintenance of the reduced glutathione pool is essential for T cell tumor control [45] and inflammatory responses [46,47]. The specific role of PDI-ERO1α relay to shape glutathione homeostasis in T cells is an area of interest.…”

Cell-mediated immune resistance in cancer

“…T cell populations expand considerably upon antigenic stimulation, followed by a period of contraction as cells targeting self-antigens are deleted. Clonal deletion presents a technical barrier for adoptive cell therapies that use T cells with tumor antigen-specific TCRs or engineered TCRs by affecting both developing and mature T cells [126,127] .…”

“…Caspase-dependent AICD relies on the interaction between Fas-expressing T cells and FasL-expressing tumor cells to trigger a caspase cleavage cascade within the T cell, leading to apoptosis [128] . Caspase-independent AICD occurs upon repetitive TCR stimulation and c-JUN N-terminal kinase activation, which triggers the release of mitochondria-derived death effectors [126,127,129] . p53 may also contribute to a mitochondria-centric cell death by activating a DNA damage response pathway consisting of DNA damage marker γH2AX upregulation and ATM activation [127] .…”

“…Caspase-independent AICD occurs upon repetitive TCR stimulation and c-JUN N-terminal kinase activation, which triggers the release of mitochondria-derived death effectors [126,127,129] . p53 may also contribute to a mitochondria-centric cell death by activating a DNA damage response pathway consisting of DNA damage marker γH2AX upregulation and ATM activation [127] . A recent study has reported the importance of a long non-coding RNA (lncRNA), NF-κB-interacting lncRNA (NKILA), in inhibiting NF-κB activity and potentiating AICD in CTLs and Th1 cells [130] .…”