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Mark J. Smyth - One of the best experts on this subject based on the ideXlab platform.
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il 21 enhances Tumor Rejection through a nkg2d dependent mechanism
Journal of Immunology, 2005Co-Authors: Rayna Takaki, Mark J. Smyth, Yoshihiro Hayakawa, Andrew J Nelson, Pallavur V Sivakumar, Steven J Hughes, Lewis L LanierAbstract:IL-21 is a cytokine that can promote the anti-Tumor responses of the innate and adaptive immune system. Mice treated with IL-21 reject Tumor cells more efficiently, and a higher percentage of mice remain Tumor-free compared with untreated controls. In this study, we demonstrate that in certain Tumor models IL-21-enhanced Tumor Rejection is NKG2D dependent. When engagement of the NKG2D receptor was prevented, either due to the lack of ligand expression on the Tumor cells or due to direct blocking with anti-NKG2D mAb treatment, the protective effects of IL-21 treatment were abrogated or substantially diminished. Specifically, IL-21 only demonstrated a therapeutic effect in mice challenged with a retinoic acid early inducible-1delta-bearing lymphoma but not in mice bearing parental RMA Tumors lacking NKG2D ligands. Furthermore, treatment with a blocking anti-NKG2D mAb largely prevented the therapeutic effect of IL-21 in mice challenged with the 4T1 breast carcinoma, the 3LL lung carcinoma, and RM-1 prostate carcinoma. By contrast, IL-21 did mediate beneficial effects against both the parental DA3 mammary carcinoma and DA3 Tumors transfected with H60, a NKG2D ligand. We also observed that IL-21 treatment could enhance RMA-retinoic acid early inducible-1delta Tumor Rejection in RAG-1(-/-) deficient mice, thereby demonstrating that the IL-21-induced protective effect can be mediated by the innate immune system and that, in this case, IL-21 does not require the adaptive immune response. Collectively, these findings suggest that IL-21 therapy may work optimally against Tumors that can elicit a NKG2D-mediated immune response.
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cutting edge granzymes a and b are not essential for perforin mediated Tumor Rejection
Journal of Immunology, 2003Co-Authors: Mark J. Smyth, Shayna E A Street, Joseph A TrapaniAbstract:Controversy still exists regarding the biological function of granzyme serine proteases released with perforin from the cytotoxic granules of NK cells and CTLs. In particular, it is not clear whether the major granzymes, A and B, play an essential role in Tumor Rejection mediated by the perforin pathway. We have now examined the relative importance of perforin and granzyme A and B clusters in five different Tumor models that stringently distinguish their importance. We conclude that granzyme A and B clusters are not essential for CTL- and NK cell-mediated Rejection of spontaneous and experimental Tumors, raising the likelihood that either perforin alone or in combination with an additional granzyme or granule component(s) mediates cytotoxicity of Tumor cells in vivo.
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cutting edge Tumor Rejection mediated by nkg2d receptor ligand interaction is dependent upon perforin
Journal of Immunology, 2002Co-Authors: Yoshihiro Hayakawa, Janice M Kelly, David H Raulet, Phillip K Darcy, Jennifer A Westwood, Andreas Diefenbach, Mark J. SmythAbstract:We have investigated the primary immunity generated in vivo by MHC class I-deficient and -competent Tumor cell lines that expressed the NKG2D ligand retinoic acid early inducible-1 (Rae-1) β. Rae-1β expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated Tumor Rejection in vivo, whereas RMA-Rae-1β Tumor cells were rejected by a combination of NK cells and CD8 + T cells. Rae-1β expression stimulated NK cell cytotoxicity and IFN-γ secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-γ, was critical for the Rejection of Rae-1β-expressing Tumor cells in vivo. This distinct requirement for perforin activity contrasts with the NK cell-mediated Rejection of MHC class I-deficient RMA-S Tumor cells expressing other activating ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing Tumor cells.
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cutting edge Tumor Rejection mediated by nkg2d receptor ligand interaction is dependent upon perforin
Journal of Immunology, 2002Co-Authors: Yoshihiro Hayakawa, Janice M Kelly, David H Raulet, Phillip K Darcy, Jennifer A Westwood, Andreas Diefenbach, Mark J. SmythAbstract:We have investigated the primary immunity generated in vivo by MHC class I-deficient and -competent Tumor cell lines that expressed the NKG2D ligand retinoic acid early inducible-1 (Rae-1) beta. Rae-1beta expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated Tumor Rejection in vivo, whereas RMA-Rae-1beta Tumor cells were rejected by a combination of NK cells and CD8(+) T cells. Rae-1beta expression stimulated NK cell cytotoxicity and IFN-gamma secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-gamma, was critical for the Rejection of Rae-1beta-expressing Tumor cells in vivo. This distinct requirement for perforin activity contrasts with the NK cell-mediated Rejection of MHC class I-deficient RMA-S Tumor cells expressing other activating ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing Tumor cells.
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induction of Tumor specific t cell memory by nk cell mediated Tumor Rejection
Nature Immunology, 2002Co-Authors: Janice M Kelly, Phillip K Darcy, Jessica L Markby, Dale I Godfrey, Kazuyoshi Takeda, Hideo Yagita, Mark J. SmythAbstract:Natural killer (NK) cells may modulate the development of adaptive immune responses, but until now there has been little evidence to support this hypothesis. We investigated the primary and secondary immunity elicited by various Tumor cell lines that express CD70 and interact with CD70 ligand (CD27), which is constitutively expressed on NK cells. CD70 expression enhanced primary Tumor Rejection in vivo as well as T cell immunity against secondary Tumor challenge. Primary Rejection of major histocompatibility complex (MHC) class I-deficient RMA-S.CD70 Tumor cells was mediated by NK cells and perforin- and interferon-gamma-dependent mechanisms. This NK cell-mediated process also efficiently evoked the subsequent development of Tumor-specific cytotoxic and T helper type 1 responses to the parental, MHC class I-sufficient, RMA Tumor cells. Thus CD27-CD70 interactions provide a key link between innate NK cell responses and adaptive T cell immunity.
Jerry Y Niederkorn - One of the best experts on this subject based on the ideXlab platform.
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role of interferon γ and cytotoxic t lymphocytes in intraocular Tumor Rejection
Journal of Leukocyte Biology, 2016Co-Authors: Ann J Ligocki, Joseph R Brown, Jerry Y NiederkornAbstract:The eye is normally an immunosuppressive environment. This condition is better known as immune privilege and protects the eye from immune-mediated inflammation of tissues that cannot regenerate. However, immune privilege creates a dilemma for the eye when intraocular neoplasms arise. In some cases, immune privilege is suspended, resulting in the immune Rejection of intraocular Tumors. This study employed a mouse model in which interferon-g–dependent intraocular Tumor Rejection occurs. We tested the hypothesis that this Rejection requires interferon-g for the generation and functional capacity of cytotoxic T lymphocyte–mediated Rejection of intraocular Tumors. Tumors grew progressively in the eyes of interferon-g knockout mice, even though the mice generated Tumor-specific cytotoxic T lymphocyte responses in the periphery. However, interferon-g knockout mice rejected Tumors that were introduced into extraocular sites. Subcutaneous Tumor immunization before intraocular challenge led to Tumor Rejection and preservation of the eye in wild-type mice. By contrast, Tumors grew progressively in the eyes of interferon-g knockout mice despite their ability to generate peripheral Tumor-specific cytotoxic T lymphocytes as well as the capacity of CD8 + T cells to enter the eye as shown by the presence of CD8 and perforin message and CD3 + CD8 + leukocytes within the Tumor-bearing eye. We found that cytotoxic T lymphocytes generated in wild-type mice and adoptively transferred into interferon-g knockout mice mediated the Rejection of intraocular Tumors in interferon-g knockout hosts. The results indicate that interferon-g is critical for the initial priming and differentiation of cytotoxic T lymphocytes residing in the periphery to produce the most effect antiTumor function within the eye. J. Leukoc. Biol. 99: 000–000; 2016.
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natural killer t cells contribute to neutrophil recruitment and ocular tissue damage in a model of intraocular Tumor Rejection
Investigative Ophthalmology & Visual Science, 2016Co-Authors: Ann J Ligocki, Jerry Y NiederkornAbstract:Purpose Immune privilege of the eye protects the nonregenerative ocular tissues from innate and adaptive immune-mediated inflammation. In the case of intraocular Tumors, immune privilege can be arrested to allow for immune-mediated Rejection. Activation of innate immune cells can contribute to necrosis of the intraocular Tumor and bystander ocular tissue. Identifying the cellular components of the innate immune system that contribute to ocular destruction, but are not needed for Tumor Rejection, provides insights into the immunopathological sequelae in intraocular Tumor Rejection. Methods Wild-type (WT), Jα18 knockout (KO) mice lacking type I natural killer T (NKT) cells, and CD1d KO mice lacking all NKT cells, were used to identify the role of type II NKT cells in intraocular Tumor Rejection immunopathology. Results CD1d KO mice had significantly lowered rates of necrotic eye destruction during Tumor Rejection compared to WT or Jα18 KO mice. Transcriptome and protein analyses revealed that CD1d KO mice had significantly lower expression of CXCL3 compared to WT or Jα18 KO mice, and this was associated with decreased neutrophil recruitment. The presence of type II NKT cells in WT or Jα18 KO mice led to increased CXCL3, which attracted neutrophils to the intraocular Tumor and culminated in destruction of the eye. Conclusions We found that type II NKT cells are critical in initiating a damaging inflammatory antiTumor response involving the recruitment of neutrophils that compromises the integrity of the eye. Loss of type II NKT cells or depleting neutrophils allows for a productive intraocular Tumor response that converts the Rejection phenotype to preserve the eye.
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ifn γ independent intraocular Tumor Rejection is mediated by a macrophage dependent process that leaves the eye intact
Journal of Leukocyte Biology, 2012Co-Authors: Terry G Coursey, Peter Chen, Jerry Y NiederkornAbstract:Intraocular Tumors reside in an immune-privileged site, yet in certain circumstances, they can undergo immune Rejection. Ocular Tumor Rejection can follow one of two pathways. One pathway is CD4 T cell-dependent and culminates in ischemic necrosis of the Tumor and phthisis (atrophy) of the eye. A second pathway is also CD4 T cell-dependent but does not inflict collateral injury to ocular tissues, and the eye is preserved. We isolated two clones of a murine Tumor, Ad5E1 that undergo profoundly different forms of immune Rejection in the eye. Clone 2.1 Tumors undergo an ischemic necrotizing form of Rejection that requires IFN-, T cells, and ocular macrophages and culminates in destruction of the eye. By contrast, the second clone of Ad5E1, clone 4, undergoes Rejection that also requires T cells and ocular macrophages, but leaves the eye in pristine condition (nonphthisical Rejection). Here, we demonstrate that nonphthisical Tumor Rejection of clone 4 Tumors is IFN-independent but requires an ocular macrophage population that contains M1 and M2 macrophages. Clone 4 Tumor-bearing eyes displayed ten- and 15-fold increases in M2- and M1-associated markers Arg1 and NO2, respectively. This is in sharp contrast to previous results with clone 2.1 Tumor Rejection, in which M2 markers were undetectable, and the eye was destroyed. These results suggest that the presence of M2 macrophages tempers the immune Rejection of intraocular Tumors and promotes immune effectors that inflict minimal injury to innocent bystander cells and thereby preserve the integrity and function of the eye. J. Leukoc. Biol. 92: 939–950; 2012.
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il 17 dependent ifn γ independent Tumor Rejection is mediated by cytotoxic t lymphocytes and occurs at extraocular sites but is excluded from the eye
Journal of Immunology, 2011Co-Authors: Terry G Coursey, Peter Chen, Jerry Y NiederkornAbstract:Although intraocular Tumors reside in an immune-privileged site where immune responses are suppressed, some Tumors are rejected. An example of this is the Rejection of intraocular adenovirus-induced (adenovirus type 5 early region 1 [Ad5E1]) Tumors in C57BL/6 mice. We previously identified an Ad5E1 Tumor clone in which the Rejection is IFN-γ dependent and culminates in the destruction of both the Tumor and the eye. Although Ad5E1 Tumors are not rejected when transplanted into the eyes of IFN-γ KO mice, they are rejected after s.c. transplantation. Thus, outside of the eye Ad5E1 Tumors elicit a form of Tumor immunity that is IFN-γ independent. In this article, we demonstrate that IFN-γ–independent s.c. Rejection requires both CD4 + and CD8 + T cells. Furthermore, s.c. Tumor Rejection requires IL-17, which is produced by IFN-γ–deficient CD4 + T cells in response to Tumor Ags (TAs). Splenocytes from CD4-depleted IFN-γ KO mice produce significantly less IL-17 compared with splenocytes from isotype-treated IFN-γ KO animals in response to TAs. Furthermore, depletion of IL-17 decreases CTL activity against Ad5E1 Tumor cells. In this model we propose that, in the absence of IFN-γ, CD4 + T cells produce IL-17 in response to TAs, which increases CTL activity that mediates Tumor Rejection; however, this does not occur in the eye. IL-6 production within the eye is severely reduced, which is consistent with the failure to induce Th17 cells within the intraocular Tumors. In contrast, the s.c. environment is replete with IL-6 and supports the induction of Th17 cells. Therefore, IFN-γ–independent Tumor Rejection is excluded from the eye and may represent a newly recognized form of ocular immune privilege.
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cd8 t cells circumvent immune privilege in the eye and mediate intraocular Tumor Rejection by a tnf α dependent mechanism
Journal of Immunology, 2007Co-Authors: Dru S. Dace, Peter Chen, Jerry Y NiederkornAbstract:Although intraocular Tumors reside in an immune-privileged environment, T cells can circumvent immune privilege and mediate Tumor Rejection without inducing damage to normal ocular tissue. In this study, we used a well-characterized Tumor, Ad5E1 (adenovirus type 5 early region 1), to analyze the role of CD8+ T cells in the pristine Rejection of intraocular Tumors. It has been previously documented that Ad5E1 Tumor Rejection can occur in the absence of CD8+ T cells. However, here we find that CD8+ T cells infiltrated intraocular Ad5E1 Tumors in C57BL/6 mice. Surprisingly, CD8+ T cells from Tumor-rejector mice could mediate intraocular Tumor Rejection following adoptive transfer to SCID mice. In determining the mechanisms behind CD8+ T cell-mediated Tumor Rejection, we discovered that antiTumor CTL activity was neither observed nor necessary for Rejection of the intraocular Tumors. CD8+ T cells from rejector mice did not produce IFN-γ in response to Ad5E1 Tumor Ags or use FasL to mediate intraocular Tumor Rejection. Also, CD8+ T cells did not use perforin or TRAIL, as CD8+ T cells from perforin knockout (KO) and TRAIL KO mice conferred protection to SCID recipient mice following adoptive transfer. We discovered that CD8+ T cells used TNF-α to mediate Tumor Rejection, because Ad5E1 Tumor cells were highly sensitive to TNF-α-induced apoptosis and CD8+ T cells from TNF-α KO mice did not protect SCID mice from progressive Ad5E1 Tumor growth. The results indicate that CD8+ T cells circumvent immune privilege and mediate intraocular Tumor Rejection by a TNF-α-dependent manner while leaving the eye intact and vision preserved.
Janice M Kelly - One of the best experts on this subject based on the ideXlab platform.
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cutting edge Tumor Rejection mediated by nkg2d receptor ligand interaction is dependent upon perforin
Journal of Immunology, 2002Co-Authors: Yoshihiro Hayakawa, Janice M Kelly, David H Raulet, Phillip K Darcy, Jennifer A Westwood, Andreas Diefenbach, Mark J. SmythAbstract:We have investigated the primary immunity generated in vivo by MHC class I-deficient and -competent Tumor cell lines that expressed the NKG2D ligand retinoic acid early inducible-1 (Rae-1) β. Rae-1β expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated Tumor Rejection in vivo, whereas RMA-Rae-1β Tumor cells were rejected by a combination of NK cells and CD8 + T cells. Rae-1β expression stimulated NK cell cytotoxicity and IFN-γ secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-γ, was critical for the Rejection of Rae-1β-expressing Tumor cells in vivo. This distinct requirement for perforin activity contrasts with the NK cell-mediated Rejection of MHC class I-deficient RMA-S Tumor cells expressing other activating ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing Tumor cells.
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cutting edge Tumor Rejection mediated by nkg2d receptor ligand interaction is dependent upon perforin
Journal of Immunology, 2002Co-Authors: Yoshihiro Hayakawa, Janice M Kelly, David H Raulet, Phillip K Darcy, Jennifer A Westwood, Andreas Diefenbach, Mark J. SmythAbstract:We have investigated the primary immunity generated in vivo by MHC class I-deficient and -competent Tumor cell lines that expressed the NKG2D ligand retinoic acid early inducible-1 (Rae-1) beta. Rae-1beta expression on class I-deficient RMA-S lymphoma cells enhanced primary NK cell-mediated Tumor Rejection in vivo, whereas RMA-Rae-1beta Tumor cells were rejected by a combination of NK cells and CD8(+) T cells. Rae-1beta expression stimulated NK cell cytotoxicity and IFN-gamma secretion in vitro, but not proliferation. Surprisingly, only NK cell perforin-mediated cytotoxicity, but not production of IFN-gamma, was critical for the Rejection of Rae-1beta-expressing Tumor cells in vivo. This distinct requirement for perforin activity contrasts with the NK cell-mediated Rejection of MHC class I-deficient RMA-S Tumor cells expressing other activating ligands such as CD70 and CD80. Thus, these results indicated that NKG2D acted as a natural cytotoxicity receptor to stimulate perforin-mediated elimination of ligand-expressing Tumor cells.
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induction of Tumor specific t cell memory by nk cell mediated Tumor Rejection
Nature Immunology, 2002Co-Authors: Janice M Kelly, Phillip K Darcy, Jessica L Markby, Dale I Godfrey, Kazuyoshi Takeda, Hideo Yagita, Mark J. SmythAbstract:Natural killer (NK) cells may modulate the development of adaptive immune responses, but until now there has been little evidence to support this hypothesis. We investigated the primary and secondary immunity elicited by various Tumor cell lines that express CD70 and interact with CD70 ligand (CD27), which is constitutively expressed on NK cells. CD70 expression enhanced primary Tumor Rejection in vivo as well as T cell immunity against secondary Tumor challenge. Primary Rejection of major histocompatibility complex (MHC) class I-deficient RMA-S.CD70 Tumor cells was mediated by NK cells and perforin- and interferon-gamma-dependent mechanisms. This NK cell-mediated process also efficiently evoked the subsequent development of Tumor-specific cytotoxic and T helper type 1 responses to the parental, MHC class I-sufficient, RMA Tumor cells. Thus CD27-CD70 interactions provide a key link between innate NK cell responses and adaptive T cell immunity.
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an essential role for Tumor necrosis factor in natural killer cell mediated Tumor Rejection in the peritoneum
Journal of Experimental Medicine, 1998Co-Authors: Mark J. Smyth, Janice M Kelly, Alan G Baxter, Heinrich Korner, Jonathon D SedgwickAbstract:Natural killer (NK) cells are thought to provide the first line of defence against Tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S Tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking Tumor necrosis factor (TNF) are also significantly defective in their Rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to Tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated Rejection of Tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− Tumor Rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.
Ibrahim M Sektioglu - One of the best experts on this subject based on the ideXlab platform.
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basophils promote Tumor Rejection via chemotaxis and infiltration of cd8 t cells
Cancer Research, 2017Co-Authors: Ibrahim M Sektioglu, Rafael Carretero, Thomas Tuting, Nadja Bulbuc, Tobias Bald, Alexander Y Rudensky, Gunter J HammerlingAbstract:Elevated numbers of regulatory T cells (Treg) in patient Tumors are known to inhibit efficient antiTumor T-cell responses. To study the mechanisms controlling Tumor Rejection, we assessed different mouse models for Treg depletion. In Foxp3DTR knock-in mice, about 99% Treg depletion was achieved, resulting in complete Rejection of transplanted HCmel12 melanomas in a CD8+ T-cell–dependent way. In contrast, about 90% Treg depletion obtained in BAC transgenic Foxp3.LuciDTR4 mice failed to induce complete Rejection of HCmel12 melanomas, demonstrating that residual Tregs were able to control CD8+ T-cell responses against the Tumor. Ninety-nine percent of Treg depletion provoked drastic changes in the Tumor microenvironment, such as strong infiltration of CD8+ T cells and basophils. IntraTumoral basophils enhanced CD8+ T-cell infiltration via production of chemokines CCL3 and CCL4; antibody-based blocking of these chemokines inhibited CD8+ T-cell infiltration. Therapeutic induction of basophilia by IL3/anti-IL3 antibody complexes, combined with transfer of CD8+ T cells, resulted in enhanced T-cell infiltration and Tumor Rejection. Our study identifies a critical role basophils play in Tumor Rejection and that this role can be exploited for therapeutic intervention. Cancer Res; 77(2); 291–302. ©2016 AACR.
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macrophage derived nitric oxide initiates t cell diapedesis and Tumor Rejection
OncoImmunology, 2016Co-Authors: Ibrahim M Sektioglu, Rafael Carretero, Noemi Bender, Christian Bogdan, Natalio Garbi, Ludmila Umansky, Katharina Urban, Magnus Von Knebeldoberitz, Viktor Umansky, Veena SomasundaramAbstract:ABSTRACTIn Tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing Tumor macrophages in T-cell infiltration and Tumor Rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on Tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS+ macrophages in Tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These ...
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macrophage derived nitric oxide initiates t cell diapedesis and Tumor Rejection
OncoImmunology, 2016Co-Authors: Ibrahim M Sektioglu, Rafael Carretero, Noemi Bender, Christian Bogdan, Natalio Garbi, Ludmila Umansky, Katharina Urban, Viktor Umansky, Magnus Von Knebeldoberitz, Veena SomasundaramAbstract:In Tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing Tumor macrophages in T-cell infiltration and Tumor Rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on Tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS+ macrophages in Tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These results will be valuable for the development of strategies designed to overcome the paucity of T-cell infiltration into Tumors that is a major obstacle in clinical cancer immunotherapy.
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eosinophils orchestrate cancer Rejection by normalizing Tumor vessels and enhancing infiltration of cd8 t cells
Nature Immunology, 2015Co-Authors: Rafael Carretero, Ibrahim M Sektioglu, Natalio Garbi, Oscar C Salgado, Philipp Beckhove, Gunter J HammerlingAbstract:Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to Tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for Tumor Rejection in the presence of Tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the Tumor, which resulted in Tumor eradication and survival. Activated eosinophils initiated substantial changes in the Tumor microenvironment, including macrophage polarization and normalization of the Tumor vasculature, which are known to promote Tumor Rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.
Veena Somasundaram - One of the best experts on this subject based on the ideXlab platform.
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macrophage derived nitric oxide initiates t cell diapedesis and Tumor Rejection
OncoImmunology, 2016Co-Authors: Ibrahim M Sektioglu, Rafael Carretero, Noemi Bender, Christian Bogdan, Natalio Garbi, Ludmila Umansky, Katharina Urban, Magnus Von Knebeldoberitz, Viktor Umansky, Veena SomasundaramAbstract:ABSTRACTIn Tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing Tumor macrophages in T-cell infiltration and Tumor Rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on Tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS+ macrophages in Tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These ...
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macrophage derived nitric oxide initiates t cell diapedesis and Tumor Rejection
OncoImmunology, 2016Co-Authors: Ibrahim M Sektioglu, Rafael Carretero, Noemi Bender, Christian Bogdan, Natalio Garbi, Ludmila Umansky, Katharina Urban, Viktor Umansky, Magnus Von Knebeldoberitz, Veena SomasundaramAbstract:In Tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing Tumor macrophages in T-cell infiltration and Tumor Rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on Tumor vessels adhesion molecules that were required for T-cell extravasation. Experiments with human endothelial cells revealed a bimodal dose-dependent effect of NO. High doses of NO donors were indeed suppressive but lower, more physiological concentrations, induced adhesion molecules in an NFkB-dependent pathway and preferentially activated transcription of genes involved in lymphocyte diapedesis. iNOS+ macrophages in Tumors appear to generate precisely the amount of NO that promotes endothelial activation and T-cell infiltration. These results will be valuable for the development of strategies designed to overcome the paucity of T-cell infiltration into Tumors that is a major obstacle in clinical cancer immunotherapy.
