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Derivation of mimetic ?? T cells endowed with cancer recognition receptors from reprogrammed ?? T cell.

ABSTRACT: Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used ?? T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these ?? T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed ?? T cell into iPSCs (?? T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-associated antigens, we used an "NK cell-promoting" protocol to differentiate ?? T-iPSCs and to induce expression of natural killer receptors (NKRs). Through such two-step strategy, mimetic ?? T cells endowed with an array of NKRs and thus designated as "?? natural killer T (?? NKT) cells" were derived. With no/low-level expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) and immune checkpoint receptors, ?? NKT cells may provide a potent "off-the-shelf" cytotoxic cell source to recognize multiple ubiquitous antigens in a broad spectrum of cancers.

SUBMITTER: Zeng J

PROVIDER: S-EPMC6508724 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Derivation of mimetic γδ T cells endowed with cancer recognition receptors from reprogrammed γδ T cell.

Zeng Jieming J Tang Shin Yi SY Wang Shu S

PloS one 20190509 5

Using induced pluripotent stem cells (iPSCs) to derive chimeric antigen receptor-modified T (CAR-T) cells has great industrial potential. A previous study used αβ T cell-derived CAR-modified iPSCs to produce CAR-T cells. However, these αβ T cells are restricted to autologous use and only recognize single cancer antigen. To make CAR-T alternative for allogeneic use, we reprogrammed γδ T cell into iPSCs (γδ T-iPSCs) to circumvent the risk of graft-versus-host disease. To target multiple cancer-ass ...[more]

PMID: 31071196

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Project description:Acquired immune evasion is one of the mechanisms that contributes to the dismal prognosis of cancer. Recently, we observed that different γδ T cell subsets as well as CD8+ αβ T cells infiltrate the pancreatic tissue. Interestingly, the abundance of γδ T cells was reported to have a positive prognostic impact on survival of cancer patients. Since γδ T cells utilize TNF-related apoptosis inducing ligand (TRAIL) for killing of tumor cells in addition to granzyme B and perforin, we investigated the role of the TRAIL-/TRAIL-R system in γδ T cell-cytotoxicity toward pancreatic ductal adenocarcinoma (PDAC) and other cancer cells. Coculture of the different cancer cells with γδ T cells resulted in a moderate lysis of tumor cells. The lysis of PDAC Colo357 cells was independent of TRAIL as it was not inhibited by the addition of neutralizing anti-TRAIL antibodies or TRAIL-R2-Fc fusion protein. In accordance, knockdown (KD) of death receptors TRAIL-R1 or TRAIL-R2 in Colo357 cells had no effect on γδ T cell-mediated cytotoxicity. However, KD of decoy receptor TRAIL-R4, which robustly enhanced TRAIL-induced apoptosis, interestingly, almost completely abolished the γδ T cell-mediated lysis of these tumor cells. This effect was associated with a reduced secretion of granzyme B by γδ T cells and enhanced PGE2 production as a result of increased expression level of synthetase cyclooxygenase (COX)-2 by TRAIL-R4-KD cells. In contrast, knockin of TRAIL-R4 decreased COX-2 expression. Importantly, reduced release of granzyme B by γδ T cells cocultured with TRAIL-R4-KD cells was partially reverted by bispecific antibody [HER2xCD3] and led in consequence to enhanced lysis of tumor cells. Likewise, inhibition of COX-1 and/or COX-2 partially enhanced γδ T cell-mediated lysis of TRAIL-R4-KD cells. The combination of bispecific antibody and COX-inhibitor completely restored the lysis of TRAIL-R4-KD cells by γδ T cells. In conclusion, we uncovered an unexpected novel role of TRAIL-R4 in tumor cells. In contrast to its known pro-tumoral, anti-apoptotic function, TRAIL-R4 augments the anti-tumoral cytotoxic activity of γδ T cells.

Project description:Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.

Dataset Information

Derivation of mimetic ?? T cells endowed with cancer recognition receptors from reprogrammed ?? T cell.

Publications

Derivation of mimetic γδ T cells endowed with cancer recognition receptors from reprogrammed γδ T cell.

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