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Targeting gamma delta T cells for cancer immunotherapy: bench to bedside.

Gogoi D, Chiplunkar SV - Indian J. Med. Res. (2013)

Bottom Line: Activated γδ T cells release copious amounts of interferon (IFN)-γ and tumour necrosis factor (TNF)-α and exhibit potent anti-tumour activity.Combination of γδ T cells with therapeutic monoclonal antibodies can efficiently mediate antibody dependent cellular cytotoxicity against tumours.These features makes γδ T cells attractive mediator of cancer immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.

ABSTRACT
γδ T lymphocytes represent a minor subset of peripheral blood in humans (<10%). γδ T cells expressing Vγ9Vδ2 T cell receptor recognise the endogenous pool of isopentenyl pyrophosphate (IPP) that is overproduced in cancer cells as a result of dysregulated mevalonate pathway. Aminobisphosphonates increase the endogenous pool of IPP in cells by blocking the enzyme farnesyl pyrophosphate synthase (FPPS) of the mevalonate pathway. Activated γδ T cells release copious amounts of interferon (IFN)-γ and tumour necrosis factor (TNF)-α and exhibit potent anti-tumour activity. Combination of γδ T cells with therapeutic monoclonal antibodies can efficiently mediate antibody dependent cellular cytotoxicity against tumours. These features makes γδ T cells attractive mediator of cancer immunotherapy. We review here, the basic properties and importance of γδ T cells in tumour immunity, and highlight the key advances in anti-tumour effector functions of γδ T cells achieved over the last few years and also summarize the results of the clinical trials that have been done till date. Future immunotherapeutic approach utilizing γδ T cells holds considerable promise for treatment of different types of cancer.

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Related in: MedlinePlus

Mechanism underlying γδ T cell killing of tumours: γδ T cell receptor (TCR) interacts with isopentenyl pyrophosphate (IPP) generated through the mevalonate pathway in tumours. Bisphosphonates inhibits farnesyl pyrophosphate synthase (FPPS) leading to increased endogenous pool of IPP and dimethylalleyl pyrophosphate (DMAPP) in tumour cells. γδ T cells recognize heat shock proteins (HSPs) and MHC class I chain-related molecules (MICA/B) or UL-16 binding protein ULBP expressed on tumour cells via their TCR and natural killer group 2, member D protein (NKG2D) receptors, respectively. Perforin released from activated γδ T cells lyse the tumour cell. γδ T cells can also kill tumour cells through antibody dependent cellular cytotoxicity (ADCC). γδ T cells expressing CD16 (FCγRIII) interacts with tumour associated antigens (TAA) via specific monoclonal antibodies and mediate ADCC. Cytokines like interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) released by γδ T cells can recruit other immune cells (bystander effect).
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Figure 1: Mechanism underlying γδ T cell killing of tumours: γδ T cell receptor (TCR) interacts with isopentenyl pyrophosphate (IPP) generated through the mevalonate pathway in tumours. Bisphosphonates inhibits farnesyl pyrophosphate synthase (FPPS) leading to increased endogenous pool of IPP and dimethylalleyl pyrophosphate (DMAPP) in tumour cells. γδ T cells recognize heat shock proteins (HSPs) and MHC class I chain-related molecules (MICA/B) or UL-16 binding protein ULBP expressed on tumour cells via their TCR and natural killer group 2, member D protein (NKG2D) receptors, respectively. Perforin released from activated γδ T cells lyse the tumour cell. γδ T cells can also kill tumour cells through antibody dependent cellular cytotoxicity (ADCC). γδ T cells expressing CD16 (FCγRIII) interacts with tumour associated antigens (TAA) via specific monoclonal antibodies and mediate ADCC. Cytokines like interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) released by γδ T cells can recruit other immune cells (bystander effect).

Mentions: The unique features of human γδ T cells related to antigen recognition, tissue tropism, lack of antigen processing requirement and cytotoxic function make these ideal candidates for cancer immunotherapy. γδ T cells recognize increased pool of endogenous IPP (a consequence of dysregulated mevalonate pathway) in cancer cells, release IFN-γ/TNF-α and mediate cytolyic effector functions. Expression of NKG2D receptors provides a selective advantage to γδ T cells to recognize tumours that express stress induced molecules like MICA/B. This property of γδ T cells can be exploited for immunotherapy as tumours downregulate MHC molecules to evade immune recognition (Fig.). Human γδ T cells show potent cytotoxic effector functions against various types of tumours. One way to exploit γδ T cells for cancer immunotherapy is the use of synthetic phosphoantigens like BrHPP or HMBPP which can act as γδ TCR agonists. Future trials should harness bisphosphonate activated γδ T cells in combination with chemotherapy or monoclonal antibodies for treatment of solid tumours and haematologic malignancies.


Targeting gamma delta T cells for cancer immunotherapy: bench to bedside.

Gogoi D, Chiplunkar SV - Indian J. Med. Res. (2013)

Mechanism underlying γδ T cell killing of tumours: γδ T cell receptor (TCR) interacts with isopentenyl pyrophosphate (IPP) generated through the mevalonate pathway in tumours. Bisphosphonates inhibits farnesyl pyrophosphate synthase (FPPS) leading to increased endogenous pool of IPP and dimethylalleyl pyrophosphate (DMAPP) in tumour cells. γδ T cells recognize heat shock proteins (HSPs) and MHC class I chain-related molecules (MICA/B) or UL-16 binding protein ULBP expressed on tumour cells via their TCR and natural killer group 2, member D protein (NKG2D) receptors, respectively. Perforin released from activated γδ T cells lyse the tumour cell. γδ T cells can also kill tumour cells through antibody dependent cellular cytotoxicity (ADCC). γδ T cells expressing CD16 (FCγRIII) interacts with tumour associated antigens (TAA) via specific monoclonal antibodies and mediate ADCC. Cytokines like interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) released by γδ T cells can recruit other immune cells (bystander effect).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928706&req=5

Figure 1: Mechanism underlying γδ T cell killing of tumours: γδ T cell receptor (TCR) interacts with isopentenyl pyrophosphate (IPP) generated through the mevalonate pathway in tumours. Bisphosphonates inhibits farnesyl pyrophosphate synthase (FPPS) leading to increased endogenous pool of IPP and dimethylalleyl pyrophosphate (DMAPP) in tumour cells. γδ T cells recognize heat shock proteins (HSPs) and MHC class I chain-related molecules (MICA/B) or UL-16 binding protein ULBP expressed on tumour cells via their TCR and natural killer group 2, member D protein (NKG2D) receptors, respectively. Perforin released from activated γδ T cells lyse the tumour cell. γδ T cells can also kill tumour cells through antibody dependent cellular cytotoxicity (ADCC). γδ T cells expressing CD16 (FCγRIII) interacts with tumour associated antigens (TAA) via specific monoclonal antibodies and mediate ADCC. Cytokines like interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) released by γδ T cells can recruit other immune cells (bystander effect).
Mentions: The unique features of human γδ T cells related to antigen recognition, tissue tropism, lack of antigen processing requirement and cytotoxic function make these ideal candidates for cancer immunotherapy. γδ T cells recognize increased pool of endogenous IPP (a consequence of dysregulated mevalonate pathway) in cancer cells, release IFN-γ/TNF-α and mediate cytolyic effector functions. Expression of NKG2D receptors provides a selective advantage to γδ T cells to recognize tumours that express stress induced molecules like MICA/B. This property of γδ T cells can be exploited for immunotherapy as tumours downregulate MHC molecules to evade immune recognition (Fig.). Human γδ T cells show potent cytotoxic effector functions against various types of tumours. One way to exploit γδ T cells for cancer immunotherapy is the use of synthetic phosphoantigens like BrHPP or HMBPP which can act as γδ TCR agonists. Future trials should harness bisphosphonate activated γδ T cells in combination with chemotherapy or monoclonal antibodies for treatment of solid tumours and haematologic malignancies.

Bottom Line: Activated γδ T cells release copious amounts of interferon (IFN)-γ and tumour necrosis factor (TNF)-α and exhibit potent anti-tumour activity.Combination of γδ T cells with therapeutic monoclonal antibodies can efficiently mediate antibody dependent cellular cytotoxicity against tumours.These features makes γδ T cells attractive mediator of cancer immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.

ABSTRACT
γδ T lymphocytes represent a minor subset of peripheral blood in humans (<10%). γδ T cells expressing Vγ9Vδ2 T cell receptor recognise the endogenous pool of isopentenyl pyrophosphate (IPP) that is overproduced in cancer cells as a result of dysregulated mevalonate pathway. Aminobisphosphonates increase the endogenous pool of IPP in cells by blocking the enzyme farnesyl pyrophosphate synthase (FPPS) of the mevalonate pathway. Activated γδ T cells release copious amounts of interferon (IFN)-γ and tumour necrosis factor (TNF)-α and exhibit potent anti-tumour activity. Combination of γδ T cells with therapeutic monoclonal antibodies can efficiently mediate antibody dependent cellular cytotoxicity against tumours. These features makes γδ T cells attractive mediator of cancer immunotherapy. We review here, the basic properties and importance of γδ T cells in tumour immunity, and highlight the key advances in anti-tumour effector functions of γδ T cells achieved over the last few years and also summarize the results of the clinical trials that have been done till date. Future immunotherapeutic approach utilizing γδ T cells holds considerable promise for treatment of different types of cancer.

Show MeSH
Related in: MedlinePlus