scholarly journals Impaired in vitro Interferon-γ production in patients with visceral leishmaniasis is improved by inhibition of PD1/PDL-1 ligation

2021 ◽  
Author(s):  
Yegnasew Takele ◽  
Emebet Adem ◽  
Susanne Ursula Franssen ◽  
Rebecca Womersley ◽  
Myrsini Kaforou ◽  
...  
Keyword(s):  
T Cells ◽  
Visceral Leishmaniasis ◽  
Immune Checkpoint ◽  
Leishmania Donovani ◽  
Checkpoint Inhibitors ◽  
Interferon Γ ◽  
Ifn Gamma ◽  
Programmed Cell Death 1 ◽  
Leishmania Parasites

Visceral leishmaniasis (VL) is a neglected tropical disease that causes substantial morbidity and mortality and is a growing health problem in Ethiopia, where this study took place. Most individuals infected with Leishmania donovani parasites will stay asymptomatic, but some develop VL that, if left untreated, is almost always fatal. This stage of the disease is associated with a profound immunosuppression, characterised by impaired production of Interferon-gamma (IFN-gamma), a cytokine that plays a key role in the control of Leishmania parasites, and high expression levels of an inhibitory receptor, programmed cell death 1 (PD1) on CD4+ T cells. Here, we tested the contribution of the interaction between the immune checkpoint PD1 and its ligand PDL-1 on the impaired production of IFN-gamma in VL patients. Our results show that in the blood of VL patients, not only CD4+, but also CD8+ T cells express high levels of PD1 at the time of VL diagnosis. Next, we identified PDL-1 expression on different monocyte subsets and neutrophils and show that PDL-1 levels were significantly increased in VL patients. PD1/PDL-1 inhibition resulted in significantly increased production of IFN-gamma, suggesting that therapy using immune checkpoint inhibitors might improve disease control in these patients.

scholarly journals Interleukin 2 is an Upstream Regulator of CD4+ T Cells From Visceral Leishmaniasis Patients With Therapeutic Potential

2019 ◽  
Vol 220 (1) ◽  
pp. 163-173 ◽  
Author(s):  
Shashi Bhushan Chauhan ◽  
Rebecca Faleiro ◽  
Rajiv Kumar ◽  
Susanna Ng ◽  
Bhawana Singh ◽  
...  
Keyword(s):  
T Cells ◽  
Visceral Leishmaniasis ◽  
Cd4 T Cells ◽  
Leishmania Donovani ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Interferon Γ ◽  
Immune Functions ◽  
T Regulatory Cell ◽  
Upstream Regulator

Abstract Control of visceral leishmaniasis (VL) caused by Leishmania donovani requires interferon-γ production by CD4+ T cells. In VL patients, antiparasitic CD4+ T-cell responses are ineffective for unknown reasons. In this study, we measured the expression of genes associated with various immune functions in these cells from VL patients and compared them to CD4+ T cells from the same patients after drug treatment and from endemic controls. We found reduced GATA3, RORC, and FOXP3 gene expression in CD4+ T cells of VL patients, associated with reduced Th2, Th17, and FOXP3+CD4+ T regulatory cell frequencies in VL patient blood. Interleukin 2 (IL-2) was an important upstream regulator of CD4+ T cells from VL patients, and functional studies demonstrated the therapeutic potential of IL-2 for improving antiparasitic immunity. Together, these results provide new insights into the characteristics of CD4+ T cells from VL patients that can be used to improve antiparasitic immune responses.

scholarly journals Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells

2019 ◽  
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Jun Sasaki ◽  
Chika Kuroda ◽  
Haruka Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Volume ◽  
Tumour Microenvironment ◽  
Osteosarcoma Cell

Abstract Background: There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods: In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. Results: We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions: Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment.

scholarly journals Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells

2019 ◽  
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Jun Sasaki ◽  
Chika Kuroda ◽  
Haruka Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Volume ◽  
Osteosarcoma Cell ◽  
The Difference

Abstract Background: There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods: In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumor by Flowcytometry. Results: We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumor microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions: Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment. keywords: PD-1, Treg, osteosarcoma, anti-PD-1 antibody.

scholarly journals Transforming Growth Factor β and Immunosuppression in Experimental Visceral Leishmaniasis

1998 ◽  
Vol 66 (3) ◽  
pp. 1233-1236 ◽  
Author(s):  
Virmondes Rodrigues ◽  
João Santana da Silva ◽  
Antonio Campos-Neto
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Spleen Cells ◽  
Immunohistochemical Studies

ABSTRACT Hamsters infected with Leishmania donovani develop a disease similar to human kala-azar. They present hypergammaglobulinemia, and their T cells do not respond to parasite antigens. This unresponsiveness has been primarily ascribed to defects in antigen-presenting cells (APCs), because these cells are unable to stimulate proliferation of parasite-specific T cells from immunized animals. In this study, we show that APCs (adherent spleen cells) fromL. donovani-infected hamsters produce high levels of the inhibitory cytokine transforming growth factor β (TGF-β). Immunohistochemical studies with an anti-TGF-β monoclonal antibody (MAb) showed that this cytokine is abundantly produced in vivo by the spleen cells of infected animals. In addition, high levels of TGF-β are produced in vitro by infected hamster cells, either spontaneously or after stimulation with parasite antigen or lipopolysaccharide. Furthermore, in vivo-infected adherent cells obtained from spleens ofL. donovani-infected hamsters caused profound inhibition of the in vitro antigen-induced proliferative response of lymph node cells from hamsters immunized with leishmanial antigens. Moreover, this inhibition was totally abrogated by the anti-TGF-β MAb. These results suggest that the immunosuppression observed in visceral leishmaniasis is, at least in part, due to the abundant production of TGF-β during the course of the infection.

scholarly journals Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Jun Sasaki ◽  
Chika Kuroda ◽  
Haruka Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Volume ◽  
Tumour Microenvironment ◽  
Osteosarcoma Cell

Abstract Background There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. Results We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment.

814 MCLA-145 (CD137xPD-L1): a potent CD137 agonist and immune checkpoint inhibitor that that does not show signs of peripheral toxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A863-A863
Author(s):  
Kees Bol ◽  
Wilfred Marissen ◽  
Jeroen Elaissais-Schaap ◽  
Paul Tacken ◽  
Steef Engels ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Drug Disposition ◽  
Checkpoint Inhibitors ◽  
Clinical Investigation ◽  
Functional Screening ◽  
Costimulatory Receptor ◽  
Starting Dose ◽  
Anti Tumor Activity

BackgroundOnly a fraction of cancer patients benefit from currently available immune checkpoint inhibitors (ICI). Attempts to improve efficacy of ICI by combining with costimulatory receptor agonists such as CD137 (4-1BB) have led to greater anti-tumor activity preclinically but have shown systemic toxicity in the clinic. MCLA-145 is a human CD137xPD-L1 bispecific common light chain antibody (bAb), identified through functional screening of agonist and ICI bAb combinations. Further, MCLA-145 can overcome Treg and macrophage suppression to potently activate T cells in these immune suppressive conditions. In two ICI insensitive xenograft models, MCLA-145 demonstrated good anti-tumor activity and CD8+ T cells were enriched in tumors post treatment (indicative of intratumor expansion and recruitment). No signs of GvHD were observed in mice following treatment with MCLA-145 in contrast to that seen in animals treated with other ICI mAbs.MethodsThe EC30 from an in vitro T cell transactivation assay based on IFNg was used as an estimate of the MABEL for MCLA-145. A 2 compartment PK model coupled to a target-mediated drug disposition component was generated based on the available cynomolgus monkey PK data.ResultsRepeated doses of MCLA-145 up to 100 mg/kg/wk in cynomolgus monkeys were well tolerated without major adverse effects, and dose-dependent increases in serum MCLA-145 concentrations were observed. Following allometric scaling, the model was used to predict exposure in humans following MCLA-145 IV given over 2-hours every 2 weeks, including the starting dose for the FIH trial.ConclusionsConditional activation of CD137 signaling by MCLA-145, triggered by a neighboring target cell expressing of PD-L1, may provide both improved efficacy and safety. MCLA-145 is currently undergoing clinical investigation (NCT03922204).

scholarly journals GD2 or HER2 targeting T cell engaging bispecific antibodies to treat osteosarcoma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Jeong A. Park ◽  
Nai-Kong V. Cheung
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Control ◽  
Osteosarcoma Cell

Abstract Background The cure rate for metastatic osteosarcoma has not substantially improved over the past decades. Clinical trials of anti-HER2 trastuzumab or anti-GD2 dinutuximab for metastatic or refractory osteosarcoma were not successful, and neither was immune checkpoint inhibitors (ICIs). Methods We tested various target antigen expressions on osteosarcoma cell lines using flow cytometry and analyzed in vitro T cell engaging BsAb (T-BsAb)-dependent T cell-mediated cytotoxicity using 4-h 51Cr release assay. We tested in vivo anti-tumor activities of T-BsAb targeting GD2 or HER2 in established osteosarcoma cell line or patient-derived xenograft (PDX) mouse models carried out in BALB-Rag2−/−IL-2R-γc-KO (BRG) mice. We also generated ex vivo BsAb-armed T cells (EATs) and studied their tumor-suppressive effect against osteosarcoma xenografts. In order to improve the anti-tumor response, ICIs, anti-human PD-1 (pembrolizumab) or anti-human PD-L1 (atezolizumab) antibodies were tested their synergy with GD2- or HER2-BsAb against osteosarcoma. Results GD2 and HER2 were chosen from a panel of surface markers on osteosarcoma cell lines and PDXs. Anti-GD2 BsAb or anti-HER2 BsAb exerted potent anti-tumor effect against osteosarcoma tumors in vitro and in vivo. T cells armed with anti-GD2-BsAb (GD2-EATs) or anti-HER2-BsAb (HER2-EATs) showed significant anti-tumor activities as well. Anti-PD-L1 combination treatment enhanced BsAb-armed T cell function in vivo and improved tumor control and survival of the mice, when given sequentially and continuously. Conclusion Anti-GD2 and anti-HER2 BsAbs were effective in controlling osteosarcoma. These data support the clinical investigation of GD2 and HER2 targeted T-BsAb treatment in combination with immune checkpoint inhibitors, particularly anti-PD-L1, in patients with osteosarcoma to improve their treatment outcome.

scholarly journals Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells

2019 ◽  
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Jun Sasaki ◽  
Chika Kuroda ◽  
Haruka Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Volume ◽  
Osteosarcoma Cell ◽  
The Difference

Abstract Background: There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods: In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumor by Flowcytometry. Results: We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumor microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions: Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment. keywords: PD-1, Treg, osteosarcoma, anti-PD-1 antibody.

Altered Expression of Immune Checkpoint Molecules Including Programmed Cell Death-1 (PD-1) and Its Ligands PD-L1/PD-L2 in Waldenstrom's Macroglobulinemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1772-1772 ◽  
Author(s):  
Shahrzad Jalali ◽  
Tammy Price-Troska ◽  
Anne J. Novak ◽  
Stephen M Ansell
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Immune Checkpoint Molecules ◽  
Programmed Cell Death 1

Abstract Waldenstrom's Macroglobulinemia (WM) is an indolent B-cell malignancy that is characterized by bone marrow infiltration of lymphoplasmacytic cells and excessive synthesis of IgM. Despite improved treatment strategies and increased understanding of the underlying molecular mechanisms contributing to malignant disease progression, WM remains incurable. While whole exome sequencing analysis has revealed the genomic events associated with malignant B cell transformation in WM, the bone marrow (BM) microenvironment is also emerging as a major player in the pathogenesis of WM. Previously, our lab has reported that an array of cytokines, including IL-21 and IL-6 are increased in the WM BM and such increases are associated with high proliferation rates and IgM secretion by WM cells. In this study, we aimed to identify how immune checkpoint molecules in the BM microenvironment, specifically programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2, contribute to malignant cell expansion in WM. Using Real-Time PCR analysis, we show that the expression of PD-1, PD-L1 and PD-L2 are all significantly elevated in the cells of WM BM as compared to their normal BM counterparts. Interestingly, PD-L1 expression is also upregulated in the malignant WM cells. These findings were further confirmed by flow cytometry analysis. Subsequent in vitro analysis showed that PD-L1 and PD-L2 are cleaved from the WM cells and these soluble ligands (sPD-L1 and sPD-L2) are able to bind to the cells in the BM microenvironment, including T-cells. This results in reduced activation and proliferation of T-cells, and is accompanied by a reduction in cyclin A and p-ERK levels. In validation of the in vitro data, we also found sPD-L1 and sPD-L2 in the bone marrow plasma obtained from WM patients. While sPD-L2 was found to be present in both WM and normal BM plasma (though in a reduced level in WM), sPD-L1 was exclusive to the WM samples, implying that the function of these molecules are differentially regulated in WM. Furthermore, overexpression of PD-L1 in a WM cell line, MWCL.1, resulted in an increase in IgM secretion. Interestingly, treatment with IL-21 increased the expression of PD-L1 in WM cells, indicating that elevated IL-21 in WM BM could contribute to increased expression of PD-L1 by malignant WM cells. In summary, our data support a role for PD-1 ligands as immune regulatory molecules in WM. Further studies are ongoing to explore the molecular mechanisms by which PD-1/PD-L1/PD-L2 signaling affects the pathophysiology of WM cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells

2019 ◽  
Author(s):  
Kazushige Yoshida ◽  
Masanori Okamoto ◽  
Jun Sasaki ◽  
Chika Kuroda ◽  
Haruka Ishida ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Volume ◽  
Tumour Microenvironment ◽  
Osteosarcoma Cell

Abstract Background: There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. Methods: In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. Results: We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. Conclusions: Here we clarify for the first time an additional mechanism of anti-tumour effect—as exerted by anti-PD-1 antibody decreasing Treg— we anticipate that our findings will lead to the development of new methods for cancer treatment.

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