In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

Schilbach, Karin; Welker, Christian; Krickeberg, Naomi; Kaißer, Carlotta; Schleicher, Sabine; Hashimoto, Hisayoshi

doi:10.3390/cancers12010130

Cited by 21 publications

(22 citation statements)

References 56 publications

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“…The synergistic function of IL-12 and IL-18 in inducing the IFN-γ production of T cells and NK cells has been demonstrated ( 96 – 99 ). Similarly, IL-12 and IL-18 also induced the production of IFN-γ and increased cytotoxicity in γδT cells in an antigen-independent manner ( Figure 3 ) ( 100 , 101 ). However, the combination of IL-12 and IL-18 led to the upregulation of TIM3 on γδT cells ( 102 ).…”

Section: Cytokine-mediated Regulation Of γδT Cell Functionmentioning

confidence: 86%

Targeting Cytokine Signals to Enhance γδT Cell-Based Cancer Immunotherapy

et al. 2022

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γδT cells represent a small percentage of T cells in circulation but are found in large numbers in certain organs. They are considered to be innate immune cells that can exert cytotoxic functions on target cells without MHC restriction. Moreover, γδT cells contribute to adaptive immune response via regulating other immune cells. Under the influence of cytokines, γδT cells can be polarized to different subsets in the tumor microenvironment. In this review, we aimed to summarize the current understanding of antigen recognition by γδT cells, and the immune regulation mediated by γδT cells in the tumor microenvironment. More importantly, we depicted the polarization and plasticity of γδT cells in the presence of different cytokines and their combinations, which provided the basis for γδT cell-based cancer immunotherapy targeting cytokine signals.

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Section: Cytokine-mediated Regulation Of γδT Cell Functionmentioning

confidence: 86%

Targeting Cytokine Signals to Enhance γδT Cell-Based Cancer Immunotherapy

et al. 2022

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“…Therefore, CIS can result from novel therapeutic approaches that link, for instance, radiotherapy to an otherwise sole but still efficient immunotherapy [108]. In the context of cell-based immunotherapy, it was also recently shown that gamma delta (γδ) T cells bear a promising anti-tumor activity [109]. The study demonstrated that the TCR-independent stimulation of γδ T cells with cytokines such as IL-2, IL-12, and IL-18 enhanced their anti-tumoral potential.…”

Section: Cytokine-induced Senescence (Cis)mentioning

confidence: 99%

“…The study demonstrated that the TCR-independent stimulation of γδ T cells with cytokines such as IL-2, IL-12, and IL-18 enhanced their anti-tumoral potential. This is achieved as γδ T cells do not only induce apoptosis through cytotoxic factors such as granzymes or perforin, but also tumor cell senescence through the production of IFN-γ and TNF [109].…”

Section: Cytokine-induced Senescence (Cis)mentioning

confidence: 99%

“…Induction of senescence (via p16 or p21 upregulation) [26,126] Human cancer cell lines (bladder, melanoma, and breast) IL-2/IL-12/IL-18-stimulated γδ T cells (via secretion of IFN-γ + TNF) Induction of senescence (via p21 upregulation) [109] Human melanoma cell lines Co-culture-derived supernatants from nonclassical monocytes (slanMo) and NK cells (via secretion of IFN-γ + TNF) Induction of senescence (via p21 upregulation) [120] Murine aortic endothelial cells (MAECs) Th17 cells/IL-17A Induction of senescence (via NF-κB/p53/Rb pathway) [124] Human breast cancer cell line IL-32θ Induction of senescence (mechanism unclear) [125] In addition to the direct effects of the cytokines, immune-mediated cancer control and senescence induction can also be achieved and reinforced by the use of immune checkpoint inhibitors [26]. While blocking antibodies directed against LAG-3 and PD-L1 were sufficient to induce senescence in tumor cells, a combination with an adoptive transfer of TAA-specific Th1 cells further increased this effect.…”

Section: Induction Of Senescence and Apoptosismentioning

confidence: 99%

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Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

Rentschler

Braumüller

Briquez

et al. 2022

Cancers

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In contrast to surgical excision, chemotherapy or radiation therapy, immune checkpoint blockade therapies primarily influence cells in the tumor microenvironment, especially the tumor-associated lymphocytes and antigen-presenting cells. Besides complete remission of tumor lesions, in some patients, early tumor regression is followed by a consolidation phase where residing tumors remain dormant. Whereas the cytotoxic mechanisms of the regression phase (i.e., apoptosis, necrosis, necroptosis, and immune cell-mediated cell death) have been extensively described, the mechanisms underlying the dormant state are still a matter of debate. Here, we propose immune-mediated induction of senescence in cancers as one important player. Senescence can be achieved by tumor-associated antigen-specific T helper 1 cells, cytokines or antibodies targeting immune checkpoints. This concept differs from cytotoxic treatment, which often targets the genetic makeup of cancer cells. The immune system’s ability to establish “defensive walls” around tumors also places the tumor microenvironment into the fight against cancer. Those “defensive walls” isolate the tumor cells instead of increasing the selective pressure. They also keep the tumor cells in a non-proliferating state, thereby correcting the derailed tissue homeostasis. In conclusion, strengthening the senescence surveillance of tumors by the immune cells of the microenvironment is a future goal to dampen this life-threatening disease.

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“…5,23,[26][27][28] On the other hand, in vitro experiments and in vivo NHP studies have well established that Vγ2Vδ2 T cells, once activated by IPP or HMBPP, can be readily expanded by IL-2, IL-7, IL-15, IL-21, IL-33, and Th17-related cytokines. 17,26,[29][30][31] In fact, recent seminal studies in NHP models suggest that the phosphoantigen HMBPP-specific Vγ2Vδ2 T-cell subpopulation can respond as fast-acting T cells during microbial infections. 3,5,23 During primary microbial infections of NHPs mimicking human TB and other pathogens,…”

Section: Il-12 S I G Naling Pathway Drive S E Arly De Velopment Of mentioning

confidence: 99%

Fast‐acting γδ T‐cell subpopulation and protective immunity against infections

Shen

Huang

Qaqish

et al. 2020

Immunological Reviews

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T cells expressing γδ T cell antigen receptors (TCR) are a non-conventional T-cell population. 1-3 In humans and non-human primates (NHPs), there is a unique γδ T cell subpopulation expressing TCR heterodimer bearing Vγ2 and Vδ2 segments, termed Vγ2Vδ2 (also Vγ9Vδ2) T cells. 4 Studies carried out over several decades have addressed fundamental aspects of Vγ2Vδ2 T cells during tuberculosis (TB) and other infections. 3,5-8 Vγ2Vδ2 T cells are the sole γδ T cell subpopulation capable of recognizing phosphoantigens such as microbial (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) and the isoprenoid metabolites isopentenyl pyrophosphate (IPP). 9-11 HMBPP is produced only by the non-mevalonate pathway present in some selected microbes, such as Mycobacterium tuberculosis (Mtb), M bovis BCG and Listeria, whereas IPP can be produced by the mevalonate pathway of cholesterol synthesis in eukaryotic cells. 9,10 Phosphoantigen HMBPP-specific Vγ2Vδ2 T cells, exist only in humans and NHPs. They account for 65%-90% of total peripheral blood γδ T cells in healthy adults, play crucial role in both innate and adaptive immunity, 12-15 and mount major expansion and effector responses during infections with Mtb and other pathogens. 3,5,7,8,16,17 Recent seminal studies in NHP models demonstrate that primary TB infection or phosphoantigen with IL-2 (such as HMBPP + IL-2) administration could specifically induce expansion of Vγ2Vδ2 T cells in vivo; following expansion, they are fast-acting, multi-functional, and protective against infection with high doses of Mtb. 3,5-8 Notably, rapid recall-like expansion of Vγ2Vδ2 T cells correlates with detectable immunity against fatal tuberculosis (TB) after Mtb challenge of bacillus Calmette-Guérin (BCG)-vaccinated macaques. 3 Proof-of-concept (POC) and definitive studies are needed to address the question as to whether human Vγ2Vδ2 T cells play important roles in protective immunity against Mtb and other infections. This question has been long-standing since human γδ T cells were discovered over 30 years ago. This existing gap is largely attributed to the

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In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

Cited by 21 publications

References 56 publications

Targeting Cytokine Signals to Enhance γδT Cell-Based Cancer Immunotherapy

Targeting Cytokine Signals to Enhance γδT Cell-Based Cancer Immunotherapy

Cytokine-Induced Senescence in the Tumor Microenvironment and Its Effects on Anti-Tumor Immune Responses

Fast‐acting γδ T‐cell subpopulation and protective immunity against infections

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