scholarly journals Selection of macrophage-resistant progressor tumor variants by the normal host. Requirement for concomitant T cell-mediated immunity.

1983 ◽  
Vol 157 (2) ◽  
pp. 642-656 ◽  
Author(s):  
J L Urban ◽  
H Schreiber
Keyword(s):  
T Cell ◽  
Tumor Antigen ◽  
Specific Antigen ◽  
High Sensitivity ◽  
Immune Defense ◽  
Growth Potential ◽  
Cell Mediated Immunity ◽  
Cell Immunity

The ultraviolet radiation-induced fibrosarcoma 1591 is generally rejected by normal syngeneic mice, but occasionally the tumor succeeds in growing progressively. Analysis of these progressively growing tumors has regularly demonstrated the development of tumor variants that have acquired a heritable progressive growth potential. We have analyzed the phenotypic changes of these variants to determine which kind of selection pressure had occurred during the evolution of the variants, thus giving insight into the relative importance and hierarchy of the different immune defense mechanisms that may be operating in normal individuals as a defense against neoplastic cells. We discovered that all of the host-selected progressor variants had lost not only a strong T cell-recognized and tumor-specific antigen, but also their high sensitivity to cytotoxic macrophages. No selection for macrophage-resistance or loss of the tumor antigen was observed in 1591 tumors reisolated from idiotypically-suppressed mice or from other mice lacking tumor-specific T cell immunity. Analysis of other tumor variants selected in vitro showed that 1591 tumor cells have the potential to lose sensitivity to tumoricidal macrophages without losing the T cell-recognized tumor antigen. Thus the data suggest that T cells and macrophages act together to suppress the outgrowth of potentially malignant cells in vivo.

scholarly journals THER-05. GENETICALLY STABLE POLIOVIRUS VECTOR CARRYING H3.3K27M ANTIGEN FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA BY INTRAMUSCULAR INJECTION

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii472-iii472
Author(s):  
Mubeen Mosaheb ◽  
Daniel Landi ◽  
Elena Dobrikova ◽  
Michael Brown ◽  
Yuanfan Yang ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
Intramuscular Injection ◽  
Cd8 T Cell ◽  
Cytokine Profiles ◽  
Cell Immunity ◽  
Novel Approach ◽  
Diffuse Midline Glioma

Abstract BACKGROUND H3 K27M-mutant diffuse midline glioma (DMG) is invariably lethal. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses, in particular, are uniquely tropic for dendritic cells (DC) and potently activate DC, inducing Th1-dominant cytokine profiles, CD8 T cell immunity, and enhanced epitope presentation. Thus, poliovirus is ideally suited for vectored delivery of signature tumor neoantigens, e.g. the H3 K27M feature of DMG. However, poliovirus vector design is inherently limited by genetic instability and the underlying neuropathogenicity of poliovirus. METHODS We created a genetically stable, polio:rhinovirus chimera vector devoid of neuropathogenicity and modified for stable expression of the HLA-A2 restricted H3.3 K27M antigen (RIPO (H3.3)). RESULTS RIPO(H3.3) infects, activates, and induces H3.3K27M antigen presentation in DCs in vitro. Given intramuscularly in vivo, RIPO(H3.3) recruits and activates DCs with Th1-dominant cytokine profiles, efficiently primes H3.3K27M-specific CD8 T cells, induces antigen-specific CD8 T cell migration to the tumor site, delays tumor growth, and enhances survival in murine tumor models. CONCLUSION This novel approach leverages the unique ability of polioviruses to activate DCs while simultaneously introducing the H3.3 K27M antigen. In this way, DCs are activated optimally in situ, while being simultaneously infected to express/present tumor antigen. RIPO(H3.3), given by intramuscular injection, will be evaluated in a clinical trial for children with H3 K27M-mutant diffuse midline glioma.

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 Migration ofAntigen-Specific T Cells Away from CXCR4-Binding Human ImmunodeficiencyVirus Type 1gp120

2004 ◽  
Vol 78 (10) ◽  
pp. 5184-5193 ◽  
Author(s):  
Diana M. Brainard ◽  
William G. Tharp ◽  
Elva Granado ◽  
Nicholas Miller ◽  
Alicja K. Trocha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Active Movement ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Cell Trafficking ◽  
Hiv 1

ABSTRACT Cell-mediated immunity depends in part on appropriate migration and localization of cytotoxic T lymphocytes (CTL), a process regulated by chemokines and adhesion molecules. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode chemotactically active proteins, suggesting that dysregulation of immune cell trafficking may be a strategy for immune evasion. HIV-1 gp120, a retroviral envelope protein, has been shown to act as a T-cell chemoattractant via binding to the chemokine receptor and HIV-1 coreceptor CXCR4. We have previously shown that T cells move away from the chemokine stromal cell-derived factor 1 (SDF-1) in a concentration-dependent and CXCR4 receptor-mediated manner. Here, we demonstrate that CXCR4-binding HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific CTL, away from high concentrations of the viral protein. This migratory response is CD4 independent and inhibited by anti-CXCR4 antibodies and pertussis toxin. Additionally, the expression of X4 gp120 by target cells reduces CTL efficacy in an in vitro system designed to account for the effect of cell migration on the ability of CTL to kill their target cells. Recombinant X4 gp120 also significantly reduced antigen-specific T-cell infiltration at a site of antigen challenge in vivo. The repellant activity of HIV-1 gp120 on immune cells in vitro and in vivo was shown to be dependent on the V2 and V3 loops of HIV-1 gp120. These data suggest that the active movement of T cells away from CXCR4-binding HIV-1 gp120, which we previously termed fugetaxis, may provide a novel mechanism by which HIV-1 evades challenge by immune effector cells in vivo.

scholarly journals Binding of HMG-I(Y) Imparts Architectural Specificity to a Positioned Nucleosome on the Promoter of the Human Interleukin-2 Receptor α Gene

2000 ◽  
Vol 20 (13) ◽  
pp. 4666-4679 ◽  
Author(s):  
R. Reeves ◽  
W. J. Leonard ◽  
M. S. Nissen
Keyword(s):  
T Cell ◽  
Transcriptional Activation ◽  
Interleukin 2 ◽  
Proximal Promoter ◽  
Cell Mediated Immunity ◽  
Core Particle ◽  
The Core ◽  
Interleukin 2 Receptor

ABSTRACT Transcriptional induction of the interleukin-2 receptor alpha-chain (IL-2Rα) gene is a key event regulating T-cell-mediated immunity in mammals. In vivo, the T-cell-restricted protein Elf-1 and the general architectural transcription factor HMG-I(Y) cooperate in transcriptional regulation of the human IL-2Rα gene by binding to a specific positive regulatory region (PRRII) in its proximal promoter. Employing chromatin reconstitution analyses, we demonstrate that the binding sites for both HMG-I(Y) and Elf-1 in the PRRII element are incorporated into a strongly positioned nucleosome in vitro. A variety of analytical techniques was used to determine that a stable core particle is positioned over most of the PRRII element and that this nucleosome exhibits only a limited amount of lateral translational mobility. Regardless of its translational setting, the in vitro position of the nucleosome is such that DNA recognition sequences for both HMG-I(Y) and Elf-1 are located on the surface of the core particle. Restriction nuclease accessibility analyses indicate that a similarly positioned nucleosome also exists on the PRRII element in unstimulated lymphocytes when the IL-2Rα gene is silent and suggest that this core particle is remodeled following transcriptional activation of the gene in vivo. In vitro experiments employing the chemical cleavage reagent 1,10-phenanthroline copper (II) covalently attached to its C-terminal end demonstrate that HMG-I(Y) protein binds to the positioned PRRII nucleosome in a direction-specific manner, thus imparting a distinct architectural configuration to the core particle. Together, these findings suggest a role for the HMG-I(Y) protein in assisting the remodeling of a critically positioned nucleosome on the PRRII promoter element during IL-2Rα transcriptional activation in lymphocytes in vivo.

scholarly journals Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3096-3103 ◽  
Author(s):  
Kenrick Semple ◽  
Antony Nguyen ◽  
Yu Yu ◽  
Honglin Wang ◽  
Claudio Anasetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Protein Tyrosine Kinase ◽  
Cell Receptor ◽  
Specific Protein ◽  
Cell Immunity ◽  
Cd28 Costimulation

Abstract CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25+Foxp3+) from naive CD4 T cells (CD25−Foxp3−) by T-cell receptor stimulation with additional transforming growth factorβ (TGFβ) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2–inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling.

scholarly journals The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo

2005 ◽  
Vol 201 (4) ◽  
pp. 567-577 ◽  
Author(s):  
Jianuo Liu ◽  
Takashi Miwa ◽  
Brendan Hilliard ◽  
Youhai Chen ◽  
John D. Lambris ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
T Cell Immunity ◽  
Cell Secretion ◽  
Inhibitory Protein ◽  
Cell Immunity ◽  
Ifn Γ ◽  
Eae Model

Decay-accelerating factor ([DAF] CD55) is a glycosylphosphatidylinositol-anchored membrane inhibitor of complement with broad clinical relevance. Here, we establish an additional and unexpected role for DAF in the suppression of adaptive immune responses in vivo. In both C57BL/6 and BALB/c mice, deficiency of the Daf1 gene, which encodes the murine homologue of human DAF, significantly enhanced T cell responses to active immunization. This phenotype was characterized by hypersecretion of interferon (IFN)-γ and interleukin (IL)-2, as well as down-regulation of the inhibitory cytokine IL-10 during antigen restimulation of lymphocytes in vitro. Compared with wild-type mice, Daf1−/− mice also displayed markedly exacerbated disease progression and pathology in a T cell–dependent experimental autoimmune encephalomyelitis (EAE) model. However, disabling the complement system in Daf1−/− mice normalized T cell secretion of IFN-γ and IL-2 and attenuated disease severity in the EAE model. These findings establish a critical link between complement and T cell immunity and have implications for the role of DAF and complement in organ transplantation, tumor evasion, and vaccine development.

scholarly journals Immune Escape of Tumors in Vivo by Expression of Cellular Flice-Inhibitory Protein

1999 ◽  
Vol 190 (7) ◽  
pp. 1033-1038 ◽  
Author(s):  
Jan Paul Medema ◽  
Joan de Jong ◽  
Thorbald van Hall ◽  
Cornelis J.M. Melief ◽  
Rienk Offringa
Keyword(s):  
T Cell ◽  
Immune Escape ◽  
Cytotoxic T Cell ◽  
Tumor Control ◽  
Tumor Escape ◽  
Inhibitory Protein ◽  
Cell Immunity ◽  
Induced Apoptosis

The antiapoptotic protein cellular FLICE (Fas-associated death domain–like IL-1β–converting enzyme) inhibitory protein (cFLIP) protects cells from CD95(APO-1/Fas)-induced apoptosis in vitro and was found to be overexpressed in human melanomas. However, cytotoxic T cell–induced apoptosis, which is critically involved in tumor control in vivo, is not inhibited by cFLIP in vitro, as only CD95- and not perforin-dependent lysis is affected. This calls into question whether cFLIP is sufficient to allow escape from T cell–dependent immunity. Using two murine tumors, we directly demonstrate that cFLIP does result in escape from T cell immunity in vivo. Moreover, tumor cells are selected in vivo for elevated cFLIP expression. Therefore, our data indicate that CD95-dependent apoptosis constitutes a more prominent mechanism for tumor clearance than has so far been anticipated and that blockade of this pathway can result in tumor escape even when the perforin pathway is operational.

scholarly journals Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

2022 ◽  
Vol 12 ◽  
Author(s):  
Valentina Ceglia ◽  
Sandra Zurawski ◽  
Monica Montes ◽  
Mitchell Kroll ◽  
Aurélie Bouteau ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Class I ◽  
Agonist Activity ◽  
Cell Immunity ◽  
Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

scholarly journals Generation of dual specific bivalent BiTEs (dbBIspecific T-cell Engaging antibodies) for cellular immunotherapy

2019 ◽  
Author(s):  
Maciej Kujawski ◽  
Lin Li ◽  
Supriyo Bhattacharya ◽  
Patty Wong ◽  
Wen-Hui Lee ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Antigen ◽  
Structural Model ◽  
Molecular Size ◽  
High Yield ◽  
Cellular Immunotherapy ◽  
Target Cells ◽  
Antigen Antibody

AbstractBispecific T-cell engaging antibodies (BiTES), comprising dual anti-CD3 and anti-tumor antigen scFv fragments, are important therapeutic agents for the treatment of cancer. The dual scFv construct for BiTES requires proper protein folding while their small molecular size leads to rapid kidney clearance. Here we show that an intact (150 kDa) anti-tumor antigen antibody to CEA was joined in high yield (ca. 30%) to intact (150 kDa) anti-murine and anti-human CD3 antibodies using hinge region specific Click chemistry to form dual-specific, bivalent BiTES (db BiTES, 300 kDa). The interlocked hinge regions are compatible with a structural model that fits the electron micrographs of the 300 kDa particles. Compared to intact anti-CEA antibody, dbBiTES maintain high in vivo tumor targeting as demonstrated by PET imaging, and redirect dbBiTE coated T-cells (1 microgram/10 million cells) to kill CEA+ target cells both in vitro, and in vivo in CEA transgenic mice.

scholarly journals An optimal anti-tumor response by a novel CEA/CD3 bispecific antibody for colorectal cancers

2021 ◽  
Author(s):  
Ninghai Wang ◽  
Harshal Patel ◽  
Irene Schneider ◽  
Xin Kai ◽  
Avanish K Varshney ◽  
...  
Keyword(s):  
T Cell ◽  
Binding Affinity ◽  
Tumor Antigen ◽  
Xenograft Model ◽  
Variable Region ◽  
Dependent Manner ◽  
Cytokine Release ◽  
Complex Development

Abstract Background CD3-based bispecific T cell engagers (bsTCEs) are one of the most promising bispecific antibodies for effective cancer treatments. To elicit target-specific T cell-mediated cytotoxicity, these bsTCEs contain at least one binding unit directed against a tumor antigen and another binding unit targeting CD3 in T cell antigen receptor complex. Development of CD3-based bsTCEs, however, has been severely hampered by dose limiting toxicities due to cytokine release syndrome. To address this limitation, we developed a novel functionally trivalent TCE (t-TCE) antibody containing affinity reduced CD3 binding unit, positioned to ensure monovalent CD3 engagement, in combination with bivalent tumor antigen binding of Carcinoembryonic Antigen (CEA). Methods We modeled the variable region of anti-CD3 in the CDRs of the heavy chain and obtained CD3 binders with reduced binding affinity. Two optimized versions CEA/CD3-v1 and CEA/CD3-v2 were identified and generated in tetravalent format, characterized and compared in vitro and in vivo. Results Our lead candidate, CEA/CD3-v2, demonstrated sub-nanomolar binding and picomolar potency against a panel of CEA-expressing cancer cell lines. In addition, we detected reduced T cell cytokine release with potent cytotoxic activity. Our t-TCE CEA/CD3-v2 molecule demonstrated strong anti-tumor effect in a dose dependent manner in human PBMC xenograft model. Furthermore, combination of CEA/CD3-v2 with atezolizumab provided synergistic antitumor effect. Conclusions Because of effective tumor cell killing with various level of CEA expression and reduced cytokine release, CEA/CD3 BsTCE may greatly benefit in CEA positive cancer immunotherapy. Statement of Significance. Through optimization of CD3 binding affinity and tetravalent format with functional monovalent binding to CD3, t-TCE CEA/CD3–2 molecule not only retains high potency in vitro and in vivo, but also significantly reduces cytokine release.

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