scholarly journals 720 Targeting MARCO and IL-37R on anti-inflammatory macrophages in lung cancer blocks regulatory T cells and shift balance to support cytotoxic lymphocyte function

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A762-A762
Author(s):  
Linnéa La Fleur ◽  
Johan Botling ◽  
Fei He ◽  
Catarina Pelicano ◽  
Giorgia Palano ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Immune Suppression ◽  
Immune Cells ◽  
Cytotoxic T Cell ◽  
Lymphocyte Function ◽  
Anti Inflammatory

BackgroundThe progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment (TME). In non-small cell lung cancer (NSCLC) accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Numerous clinical trials aiming to recover T cell anti-tumor activity have been failing due to the persistence immune suppression in TME. Thus, there is a clinical need for alternative treatments targeting the suppressive function of the TME. We have previously shown that antibodies targeting the scavenger receptor MARCO reprograms the pro-tumoral TAMs in murine cancer models. Here, we investigated the immune landscape of NSCLC in the presence of MARCO expressing TAMs. We tested targeting MARCO or the tumor mechanisms inducing MARCO on human TAMs and hypothesized that targeting these mechanisms will remodel the suppressive environment and relive the anti-tumor responses to increase the efficacy of immunotherapy.MethodsTo test our hypothesis, we first investigated the immune landscape of NSCLC in the presence of pro-tumoral MARCO+TAMs compared with tumors infiltrated by MARCO-TAMs. We next used RNAseq to analyze differential gene expression in NSCLC tumors infiltrated by MARCO positive or negative macrophages. In vitro, cytokine differentiated macrophages alternatively cultured with lung cancer cell lines were co-cultured with Natural Killer (NK) cells and T cells to mimic their interaction in the TME. Later, macrophages were treated with targeting antibodies and their phenotype and function were examined prior and following interaction with other immune cells.ResultsWe found that MARCO expressing TAM numbers correlated with increased occurrence of regulatory T cell and effector T cells and decreased NK cells in NSCLC infiltrated by MARCO+TAMs. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. Studies in vitro subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an anti-inflammatory phenotype through the release of IL-37. These human MARCO expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) repolarized TAMs resulted in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells.ConclusionsIn summary, our data demonstrate a novel immune therapeutic approach targeting human TAM immune suppression of NK and T cell anti-tumor activities and remodel immune suppression.Ethics ApprovalThe study was approved by Institutional Ethics Board, approval number Dnr 2013.977-31.1.

A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3693-3701 ◽  
Author(s):  
Ypke V. J. M. van Oosterhout ◽  
Liesbeth van Emst ◽  
Anton V. M. B. Schattenberg ◽  
Wil J. M. Tax ◽  
Dirk J. Ruiter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Graft Versus Host Disease ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ricin A

Abstract This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10−8 mol/L (about 1.8 μg/mL). Because most natural killer (NK) cells are CD7+, NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have been treated with 3 to 4 infusions of 2 or 4 mg/m2 IT combination, administered intravenously at 48-hour intervals. The T1/2 was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL. Drug-associated side effects were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells.

A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3693-3701 ◽  
Author(s):  
Ypke V. J. M. van Oosterhout ◽  
Liesbeth van Emst ◽  
Anton V. M. B. Schattenberg ◽  
Wil J. M. Tax ◽  
Dirk J. Ruiter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Graft Versus Host Disease ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ricin A

This study evaluated the anti-graft versus host disease (GVHD) potential of a combination of immunotoxins (IT), consisting of a murine CD3 (SPV-T3a) and CD7 (WT1) monoclonal antibody both conjugated to deglycosylated ricin A. In vitro efficacy data demonstrated that these IT act synergistically, resulting in an approximately 99% elimination of activated T cells at 10−8 mol/L (about 1.8 μg/mL). Because most natural killer (NK) cells are CD7+, NK activity was inhibited as well. Apart from the killing mediated by ricin A, binding of SPV-T3a by itself impaired in vitro cytotoxic T-cell cytotoxicity. Flow cytometric analysis revealed that this was due to both modulation of the CD3/T-cell receptor complex and activation-induced cell death. These results warranted evaluation of the IT combination in patients with refractory acute GVHD in an ongoing pilot study. So far, 4 patients have been treated with 3 to 4 infusions of 2 or 4 mg/m2 IT combination, administered intravenously at 48-hour intervals. The T1/2 was 6.7 hours, and peak serum levels ranged from 258 to 3210 ng/mL. Drug-associated side effects were restricted to limited edema, fever, and a modest rise of creatine kinase levels. One patient developed low-titer antibodies against ricin A. Infusions were associated with an immediate drop of circulating T cells, followed by a more gradual but continuing elimination of T/NK cells. One patient mounted an extensive CD8 T-cell response directly after treatment, not accompanied with aggravating GVHD. Two patients showed nearly complete remission of GVHD, despite unresponsiveness to the extensive pretreatment. These findings justify further investigation of the IT combination for treatment of diseases mediated by T cells.

600 In vitro anticancer and immunomodulatory activities of NBT-167, a dimer of resveratrol

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A635-A635
Author(s):  
Jeffrey Zhang ◽  
Everett Henry ◽  
L Harris Zhang ◽  
Wanying Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Immune Cells ◽  
Cell Killing ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Raw264.7 Macrophages

BackgroundResveratrol (3,4’,5-trihydroxystilbene), a stilbenoid isolated from many species of plants, is widely known for its antioxidative, anti-inflammatory, immunomodulatory and anticancer activities. Recently, novel resveratrol oligomers have been isolated from various plants; their diverse structures are characterized by the polymerization of two or more resveratrol units. Little is known regarding the anticancer and immunomodulating activities of these oligomers. In this study, we designed in vitro models to compare resveratrol side by side with its natural dimer NBT-167 for their anticancer and immunological activities.MethodsWe isolated resveratrol and its dimer (NBT-167) from plants. The potency of the compounds was compared side by side using cancer cell survival assays and immunological assays with various types of human cells including cancer cell lines, PBMCs and enriched NK, gamma delta T cells, THP-1 monocytic cells, HL-60 promyelocytic leukemia cells as well as mouse RAW264.7 macrophages.ResultsNBT-167 was found to be more potent than resveratrol in inhibiting growth of various cancer cells and modulation of cytokine production from anti-IgM, LPS, PHA or SEB stimulated PBMC. Both compounds similarly enhanced IL-2 stimulated NK and gamma delta T cell killing activity against K562 cells and modulated nitric oxide production from LPS/IFN-g induced RAW264.7 macrophages and phagocytotic activity of HL-60 cells. NBT-167 was slightly more potently than resveratrol in inhibiting chemotaxis of HL-60 cells and blocking cell cycle of THP-1 and HL-60 cells at G1/S transition. In addition, NBT-167, but not resveratrol, could increase IL-2 production and T cell proliferation stimulated with anti-CD3 and anti-CD28 and synergize with anti-PD-1 antibody to increase IL-2 and IFN-gamma production in co-culture of allotypic T cells and dendric cells (MLR).ConclusionsOur data showed that NBT-167, a dimer of resveratrol, had anticancer and immunomodulatory activities such as modulation of expression of cytokines in immune cells and induction of cancer cell-killing activities of NK and gamma delta T cells. Generally, NBT-167 appeared to have higher activities than resveratrol in modulating immune cells and inhibiting cancer cells. NBT-167 could be a promising cancer immunotherapeutic agent targeting both cancer cells and immune cells.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals 708 Novel ways to exploit IL-21 to augment adoptive T cell transfer therapy against tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A737-A737
Author(s):  
Anna Cole ◽  
Guillermo Rangel RIvera ◽  
Aubrey Smith ◽  
Megan Wyatt ◽  
Brandon Ware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Striking Difference ◽  
T Cell Therapy ◽  
Cell Immunity ◽  
Emory University

BackgroundIL-21 enhances the anti-tumor capacity of adoptively transferred CD8+ T cells, while IL-2 and IL-15 impair T cell immunity by driving their expansion to a more differentiated status. Yet, these cytokines can act on many different immune cells. Given the potency of IL-21, we tested if this cytokine directly augments T cells or rather if it enhances other immune cells in the culture that indirectly improves T cell therapy.MethodsTo test this question, splenocytes from pmel-1 transgenic mice were used, as all CD8+ T cells express a transgenic TCR specific for tumor-antigen gp10025–33 overexpressed on melanoma. We then peptide activated naïve CD8+ T cells enriched or not from the spleen of pmel-1 mice and expanded them in the presence of IL-21 or IL-2 (10 ng/mL) for four days. Expanded pmel-1 from these various cultures were then restimulated with irradiated splenocytes pulsed with gp10025–33 and grown an additional seven days with IL-2 (10 ng/mL), irrespective of their initial cytokine condition. The in vitro memory phenotype, exhaustion profile, and cytokine secretion of these cultures were then assayed. Furthermore, mice bearing B16KVP melanoma tumors were infused with pmel-1 T cells expanded via these various approaches and compared for their relative capacity to engraft, persist, and regress tumor in vivo.ResultsInterestingly, we discovered that IL-21-treated T cells generated from bulk splenocytes are phenotypically and functionally distinct from IL-21-treated isolated T cells. Upon restimulation, IL-21-treated T cells from bulk splenocytes exhibited an exhausted phenotype that was like anergic IL-2-treated T cells. Moreover, few cells expressed CD62L but expressed heightened markers of suppression, including TIM3, PD-1, and EOMES. Moreover, they produced more effector molecules, including granzyme B and IFN-gamma. In vivo IL-21-treated T cells expanded from bulk splenocytes engrafted and persisted poorly, in turn mediating suboptimal regression of melanoma. Conversely, IL-21 dramatically bolstered the engraftment and antitumor activity of T cells only if they were first isolated from the spleen prior to their expansion and infusion into the animal.ConclusionsCollectively, our data shows that IL-21 may improve ACT therapy best when used directly on antitumor CD8+ T cells. Further studies will illuminate the mechanism behind this striking difference and determine whether other cell subsets reactive to IL-21 cause T cell dysfunction and/or reduced bioavailability. These findings are important for defining the best culture conditions in which to use IL-21 for ACT.AcknowledgementsWe would like to acknowledge Emory University, The Winship Cancer Institute, and the Pediatrics/Winship Flow Cytometry Core.Ethics ApprovalAll animal procedures were approved by the Institutional Animal Care and Use Committee of Emory University, protocol number 201900225.

scholarly journals Dendritic cells transduced by multiply deleted HIV-1 vectors exhibit normal phenotypes and functions and elicit an HIV-specific cytotoxic T-lymphocyte response in vitro

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1327-1333 ◽  
Author(s):  
Andreas Gruber ◽  
June Kan-Mitchell ◽  
Kelli L. Kuhen ◽  
Tetsu Mukai ◽  
Flossie Wong-Staal
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Ex Vivo ◽  
T Cell Response ◽  
Adoptive T Cell Therapy ◽  
Cytotoxic T Cell ◽  
T Cell Therapy ◽  
Hiv 1

Abstract Dendritic cells (DCs) genetically modified to continually express and present antigens may be potent physiologic adjuvants for induction of prophylactic or therapeutic immunity. We have previously shown that an env and nef deleted HIV-1 vector (HIV-1ΔEN) pseudotyped with VSV-G transduced monocyte-derived macrophages as well as CD34+ precursors of DCs. Here we extended these findings with HIV-1ΔEN to highly differentiated human DCs derived in culture from circulating monocytes (DCs). In addition, a new vector derived from HIV-1ΔEN but further deleted in its remaining accessory genes vif, vpr, and vpu(HIV-1ΔEN V3) was also tested. Both vectors efficiently transduced DCs. Transduction of DCs did not significantly alter their viability or their immunophenotype when compared with untransduced DCs. Furthermore, the phagocytic potential of immature DCs, as well as their ability to differentiate into mature DCs capable of stimulating T-cell proliferation, was not affected. Finally, DCs transduced by the HIV-1ΔEN vector were able to elicit a primary antiviral cytotoxic T-cell response in autologous CD8 T cells. These results suggest that HIV-1–based vectors expressing viral antigens may be useful for in vivo active immunization as well as ex vivo priming of cytotoxic T cells for adoptive T-cell therapy.

scholarly journals Cd2 Sets Quantitative Thresholds in T Cell Activation

1999 ◽  
Vol 190 (10) ◽  
pp. 1383-1392 ◽  
Author(s):  
Martin F. Bachmann ◽  
Marijke Barner ◽  
Manfred Kopf
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Dose Response ◽  
Response Curve ◽  
Cell Activation ◽  
Dose Response Curve ◽  
Lymphocyte Function

It has been proposed that CD2, which is highly expressed on T cells, serves to enhance T cell–antigen presenting cell (APC) adhesion and costimulate T cell activation. Here we analyzed the role of CD2 using CD2-deficient mice crossed with transgenic mice expressing a T cell receptor specific for lymphocytic choriomeningitis virus (LCMV)-derived peptide p33. We found that absence of CD2 on T cells shifted the p33-specific dose–response curve in vitro by a factor of 3–10. In comparison, stimulation of T cells in the absence of lymphocyte function–associated antigen (LFA)-1–intercellular adhesion molecule (ICAM)-1 interaction shifted the dose–response curve by a factor of 10, whereas absence of both CD2–CD48 and LFA-1–ICAM-1 interactions shifted the response by a factor of ∼100. This indicates that CD2 and LFA-1 facilitate T cell activation additively. T cell activation at low antigen density was blocked at its very first steps, as T cell APC conjugate formation, TCR triggering, and Ca2+ fluxes were affected by the absence of CD2. In vivo, LCMV-specific, CD2-deficient T cells proliferated normally upon infection with live virus but responded in a reduced fashion upon cross-priming. Thus, CD2 sets quantitative thresholds and fine-tunes T cell activation both in vitro and in vivo.

scholarly journals P01.10 IFNy secretion of adaptive and innate immune cells as a parameter to display leukaemia derived dendritic cell (DCleu) mediated immune responses in AML

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A13.1-A13
Author(s):  
LK Klauer ◽  
O Schutti ◽  
S Ugur ◽  
F Doraneh-Gard ◽  
N Rogers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Immune Cells ◽  
Gm Csf ◽  
Adaptive Immune ◽  
Cik Cells ◽  
Adaptive Immune Cells ◽  
Suitable Parameter

BackgroundMyeloid leukaemic blasts can be converted into leukaemia derived dendritic cells (DCleu) with blastmodulatory Kit-I and Kit-M, which have the competence to regularly activate T and immunoreactive cells to gain anti-leukaemic activity or rather cytotoxicity. As innate and adaptive immune responses are notably promoted by the cytokine interferon gamma (IFNy), we hypothesised that the IFNy secretion could be a suitable parameter to display DC/DCleu mediated immunologic activity and even anti-leukaemic cytotoxicity.Materials and MethodsDC/DCleu were generated from leukaemic WB with Kit-I (GM-CSF + OK-432) and Kit-M (GM-CSF + PGE1) and used to stimulate T cell enriched immunoreactive cells. Initiated anti-leukaemic cytotoxicity was investigated with a cytotoxicity fluorolysis assay (CTX). Initiated IFNy secretion of innate and adaptive immune cells (T cells, TCD4+ cells, TCD8+ cells, NKCD56+ cells, NKCD161+ cells, CIKCD56+ cells, CIKCD161+ cells and iNKT) was investigated with a cytokine secretion assay (CSA). In some cases IFNy production was additionally evaluated with an intracellular cytokine assay (ICA). Conclusively, the IFNy secretion of immunoreactive cells was correlated with the anti-leukaemic cytotoxicity.ResultsSignificant amounts of DC and DCleu as well as migratory DC and DCleu could be generated with Kit-I and Kit-M without induction of blast proliferation. T cell enriched immunoreactive cells stimulated with DC/DCleu showed an increased anti-leukaemic cytotoxicity and an increased IFNy secretion of T, NK and CIK cells compared to control. Both the CSA and ICA yielded comparable amounts of IFNy positive innate and adaptive immune cells. The correlation between the IFNy secretion of immunoreactive cells and the anti-leukaemic cytotoxicity showed a positive relationship in T cells, TCD4+ cells, TCD8+ cells and NKCD56+ cells.ConclusionsWe found blastmodulatory Kit-I and Kit-M competent to generate DC/DCleu from leukaemic WB. Stimulation of T cell enriched immunoreactive cells with DC/DCleu regularly resulted in an increased anti-leukaemic cytotoxicity and an increased IFNy dependent immunological activity of T, NK and CIK cells compared to control. Moreover the anti-leukaemic cytotoxicity positively correlated with the IFNy secretion in T cells, TCD4+ cells, TCD8+ cells, NKCD56+ cells. We therefore consider the IFNy secretion of innate and adaptive immune cells to be a suitable parameter to assess the efficacy of in vitro and potentially in vivo AML immunotherapy. The CSA in this regard proved to be a convenient and reproducible technique to detect and phenotypically characterise IFNy secreting cells of the innate and adaptive immune system.Disclosure InformationL.K. Klauer: None. O. Schutti: None. S. Ugur: None. F. Doraneh-Gard: None. N. Rogers: None. M. Weinmann: None. D. Krämer: None. A. Rank: None. C. Schmid: None. B. Eiz-Vesper: None. H.M. Schmetzer: None.

Effect of MMP9 inhibition on effector T-cell responses in a PD1-axis refractory model.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 104-104
Author(s):  
Victoria Smith ◽  
Vladi Juric ◽  
Amanda Mikels-Vigdal ◽  
Chris O'Sullivan ◽  
Maria Kovalenko ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cell Activation ◽  
Immune Cell ◽  
Single Agent ◽  
Fold Increase ◽  
Cytotoxic T Cell

104 Background: Matrix metalloproteinase 9 (MMP9) acts via diverse mechanisms to promote tumor growth and metastasis, and is a key component of the immune-suppressive myeloid inflammatory milieu. We developed a monoclonal antibody (AB0046) that inhibits murine MMP9 and assessed its mechanism of action in immunocompetent mice as a single agent, or in combination with a murine anti-PDL1 antibody. Methods: An orthotopic, syngeneic tumor model (NeuT), which models MMP9-positive myeloid infiltrate, was utilized for efficacy and pharmacodynamic studies involving RNA and T cell receptor (TCR) sequencing, and flow cytometry. Enzymatic analyses were performed on T cell chemoattractant CXCR3 ligands (CXCL9, CXCL10, and CXCL11) which were subsequently evaluated in chemotaxis assays. Results: Anti-MMP9 treatment alone or in combination with an anti-PDL1 antibody decreased primary tumor growth as compared to IgG control-treated animals (56% vs 335% tumor growth increase, p = 0.0005) or anti-PDL1 alone. Profiling of tumors by RNA sequencing revealed that inhibition of MMP9 resulted in elevated expression of genes associated with immune cell activation pathways (Hallmark Interferon Gamma Response, FDR p < 0.001). Treatment with anti-MMP9 and anti-PDL1 antibodies decreased TCR clonality, with evidence of a more diverse TCR repertoire (p = 0.005). Immunophenotyping of tumor-associated T cells by flow cytometry showed that anti-MMP9 and anti-PDL1 co-treatment promoted a 2.8-fold increase in CD3+ cells in tumors (p = 0.01), which was associated with an increase in CD4+ T cells (3.2-fold increase; p = 0.006) and CD8+ T cells (2.8-fold increase; p = 0.013). In contrast, anti-MMP9 and combination treatment resulted in a decrease in tumor-associated regulatory T cells (CD25+ FoxP3+ cells, p = 0.04). MMP9 cleavage of T cell chemoattractant ligands in vitro rendered them functionally inactive for recruitment of activated primary human effector T cells. Conclusions: Inhibition of MMP9 reduces tumor burden and promotes cytotoxic T cell infiltration in a PD1-axis refractory mouse model. The combination of nivolumab and GS-5745, a humanized anti-MMP9 inhibitory antibody, is currently being evaluated in gastric cancer (NCT02864381).

scholarly journals Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells.

1978 ◽  
Vol 147 (4) ◽  
pp. 1236-1252 ◽  
Author(s):  
T J Braciale ◽  
K L Yap
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Infectious Virus ◽  
Cytotoxic T Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell

This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.

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