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New insights into the role of NK cells in cancer immunotherapy.

Salagianni M, Baxevanis CN, Papamichail M, Perez SA - Oncoimmunology (2012)

Bottom Line: Repetitive infusions of ex vivo expanded NK cells induced antitumor T-cell responses in a metastatic lung cancer mouse model.These were further potentiated by Treg depletion.Thus the combination of NK cell-based immunotherapy with other treatment modalities in the direction of adaptive response enhancement might promote long lasting antitumor immunity.

View Article: PubMed Central - PubMed

Affiliation: Cancer Immunology and Immunotherapy Center; Saint Savas Cancer Hospital; Athens, Greece.

ABSTRACT
Repetitive infusions of ex vivo expanded NK cells induced antitumor T-cell responses in a metastatic lung cancer mouse model. These were further potentiated by Treg depletion. Thus the combination of NK cell-based immunotherapy with other treatment modalities in the direction of adaptive response enhancement might promote long lasting antitumor immunity.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Adoptive transfer of ex vivo activated and expanded NK cells can act as tumor-specific active immunotherapy, inducing long lasting anti-tumor T cell responses. NK cells can be effectively activated and expanded in vitro by cytokines in combination with GCs and/or other “stress” signals (a). Adoptively transferred activated NK cells can lyse tumor cells thus leading to the release/ production of apoptotic bodies/TAAs (b). Such tumor-derived material will be processed and presented to CD4 and CD8 T cells (i) directly, by the activated NK cells which express MHC class I and class II molecules (c) or (ii) indirectly, through NK cell-mediated activation and polarization of DCs. This can be achieved by activated NK cell-produced cytokines (IFNγ, TNFα, GM-CSF) (d) or by direct cell-to-cell contact (i.e., NKp30-NKp30L) (e). Furthermore, activated NK cells expressing costimulatory molecules (e.g., CD86, OX40L, etc) can provide efficient costimulation to T cells (through CD28, OX40, etc) (f). The concerted action of cytokines produced by the activated NKs and DCs (IFNγ, IL-12) (g) will support Th1 responses. The effective priming and restimulation of T cells by NK cells and/or DCs will induce the proliferation and differentiation of CD4+ and CD8+ into effector/memory and central memory cells that can confer long lasting antitumor immunity (h). Improvement of these responses can be achieved through inhibition of immunomodulatory mechanisms (e.g., Treg cell and MDSC elimination/ inhibition, anti-CTLA4 or anti-PD1 targeting etc) as applied in other vaccination strategies (e.g., peptide vaccines, whole cell vaccines, DC-based vaccines etc.).
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Figure 1: Figure 1. Adoptive transfer of ex vivo activated and expanded NK cells can act as tumor-specific active immunotherapy, inducing long lasting anti-tumor T cell responses. NK cells can be effectively activated and expanded in vitro by cytokines in combination with GCs and/or other “stress” signals (a). Adoptively transferred activated NK cells can lyse tumor cells thus leading to the release/ production of apoptotic bodies/TAAs (b). Such tumor-derived material will be processed and presented to CD4 and CD8 T cells (i) directly, by the activated NK cells which express MHC class I and class II molecules (c) or (ii) indirectly, through NK cell-mediated activation and polarization of DCs. This can be achieved by activated NK cell-produced cytokines (IFNγ, TNFα, GM-CSF) (d) or by direct cell-to-cell contact (i.e., NKp30-NKp30L) (e). Furthermore, activated NK cells expressing costimulatory molecules (e.g., CD86, OX40L, etc) can provide efficient costimulation to T cells (through CD28, OX40, etc) (f). The concerted action of cytokines produced by the activated NKs and DCs (IFNγ, IL-12) (g) will support Th1 responses. The effective priming and restimulation of T cells by NK cells and/or DCs will induce the proliferation and differentiation of CD4+ and CD8+ into effector/memory and central memory cells that can confer long lasting antitumor immunity (h). Improvement of these responses can be achieved through inhibition of immunomodulatory mechanisms (e.g., Treg cell and MDSC elimination/ inhibition, anti-CTLA4 or anti-PD1 targeting etc) as applied in other vaccination strategies (e.g., peptide vaccines, whole cell vaccines, DC-based vaccines etc.).

Mentions: Considering that adoptively transferred NK cells would act, either indirectly, through cross-talk with dendritic cells (DC)4 or directly, as antigen presenting cells (APC),4,5 to trigger priming of tumor-specific T cells (Fig. 1), we presumed that repeated administrations of ex vivo expanded NK cells would act as repeated anti-tumor “vaccines.” Indeed, after four weekly NK cell infusions we were able to detect memory systemic T cell responses against the syngeneic CT26 tumor cells, either by in vitro testing of splenic T cell reactivity or by rechallenging experimental animals with tumor cells in another site of the body.6


New insights into the role of NK cells in cancer immunotherapy.

Salagianni M, Baxevanis CN, Papamichail M, Perez SA - Oncoimmunology (2012)

Figure 1. Adoptive transfer of ex vivo activated and expanded NK cells can act as tumor-specific active immunotherapy, inducing long lasting anti-tumor T cell responses. NK cells can be effectively activated and expanded in vitro by cytokines in combination with GCs and/or other “stress” signals (a). Adoptively transferred activated NK cells can lyse tumor cells thus leading to the release/ production of apoptotic bodies/TAAs (b). Such tumor-derived material will be processed and presented to CD4 and CD8 T cells (i) directly, by the activated NK cells which express MHC class I and class II molecules (c) or (ii) indirectly, through NK cell-mediated activation and polarization of DCs. This can be achieved by activated NK cell-produced cytokines (IFNγ, TNFα, GM-CSF) (d) or by direct cell-to-cell contact (i.e., NKp30-NKp30L) (e). Furthermore, activated NK cells expressing costimulatory molecules (e.g., CD86, OX40L, etc) can provide efficient costimulation to T cells (through CD28, OX40, etc) (f). The concerted action of cytokines produced by the activated NKs and DCs (IFNγ, IL-12) (g) will support Th1 responses. The effective priming and restimulation of T cells by NK cells and/or DCs will induce the proliferation and differentiation of CD4+ and CD8+ into effector/memory and central memory cells that can confer long lasting antitumor immunity (h). Improvement of these responses can be achieved through inhibition of immunomodulatory mechanisms (e.g., Treg cell and MDSC elimination/ inhibition, anti-CTLA4 or anti-PD1 targeting etc) as applied in other vaccination strategies (e.g., peptide vaccines, whole cell vaccines, DC-based vaccines etc.).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376993&req=5

Figure 1: Figure 1. Adoptive transfer of ex vivo activated and expanded NK cells can act as tumor-specific active immunotherapy, inducing long lasting anti-tumor T cell responses. NK cells can be effectively activated and expanded in vitro by cytokines in combination with GCs and/or other “stress” signals (a). Adoptively transferred activated NK cells can lyse tumor cells thus leading to the release/ production of apoptotic bodies/TAAs (b). Such tumor-derived material will be processed and presented to CD4 and CD8 T cells (i) directly, by the activated NK cells which express MHC class I and class II molecules (c) or (ii) indirectly, through NK cell-mediated activation and polarization of DCs. This can be achieved by activated NK cell-produced cytokines (IFNγ, TNFα, GM-CSF) (d) or by direct cell-to-cell contact (i.e., NKp30-NKp30L) (e). Furthermore, activated NK cells expressing costimulatory molecules (e.g., CD86, OX40L, etc) can provide efficient costimulation to T cells (through CD28, OX40, etc) (f). The concerted action of cytokines produced by the activated NKs and DCs (IFNγ, IL-12) (g) will support Th1 responses. The effective priming and restimulation of T cells by NK cells and/or DCs will induce the proliferation and differentiation of CD4+ and CD8+ into effector/memory and central memory cells that can confer long lasting antitumor immunity (h). Improvement of these responses can be achieved through inhibition of immunomodulatory mechanisms (e.g., Treg cell and MDSC elimination/ inhibition, anti-CTLA4 or anti-PD1 targeting etc) as applied in other vaccination strategies (e.g., peptide vaccines, whole cell vaccines, DC-based vaccines etc.).
Mentions: Considering that adoptively transferred NK cells would act, either indirectly, through cross-talk with dendritic cells (DC)4 or directly, as antigen presenting cells (APC),4,5 to trigger priming of tumor-specific T cells (Fig. 1), we presumed that repeated administrations of ex vivo expanded NK cells would act as repeated anti-tumor “vaccines.” Indeed, after four weekly NK cell infusions we were able to detect memory systemic T cell responses against the syngeneic CT26 tumor cells, either by in vitro testing of splenic T cell reactivity or by rechallenging experimental animals with tumor cells in another site of the body.6

Bottom Line: Repetitive infusions of ex vivo expanded NK cells induced antitumor T-cell responses in a metastatic lung cancer mouse model.These were further potentiated by Treg depletion.Thus the combination of NK cell-based immunotherapy with other treatment modalities in the direction of adaptive response enhancement might promote long lasting antitumor immunity.

View Article: PubMed Central - PubMed

Affiliation: Cancer Immunology and Immunotherapy Center; Saint Savas Cancer Hospital; Athens, Greece.

ABSTRACT
Repetitive infusions of ex vivo expanded NK cells induced antitumor T-cell responses in a metastatic lung cancer mouse model. These were further potentiated by Treg depletion. Thus the combination of NK cell-based immunotherapy with other treatment modalities in the direction of adaptive response enhancement might promote long lasting antitumor immunity.

No MeSH data available.


Related in: MedlinePlus