Oral IL-10 suppresses colon carcinogenesis via elimination of pathogenicCD4+T-cells and induction of antitumor CD8+T-cell activity

LINC01355 has been demonstrated to be dysregulated in several cancers. However, the exact molecular function of LINC01355 in the pathogenesis of OSCC remains unstudied. Here, we reported the effect of LINC01355 in OSCC and investigated the mechanisms. Firstly, we found that the results indicated LINC01355 was increased in OSCC cells. Knockdown of LINC01355 repressed OSCC cell proliferation, migration, and invasion. Recently, immunotherapy is a significant method for the treatment of cancers, in which CD8+ T cells exhibit a significant role. The influence of LINC01355 on the antitumor activity of CD8+ T cells was also focused in this study. As shown, the silence of LINC01355 could repress OSCC tumor growth via inducing CD8+ T cell immune responses. In addition, we found that downregulation of LINC01355 significantly restrained CD8+ T cell apoptosis, induced CD8+ T cell percentage, and enhanced the cytolysis activity when cocultured with OSCC cells. It has been reported that the Notch pathway represses CD8+ T cell activity in cancer patients. In our present study, we displayed that lack of LINC01355 suppressed OSCC malignant behaviors and enhanced the antitumor activity of CD8+ T cells via inactivating Notch signaling. We showed that decreased LINC01355 significantly restrained the Notch signal via a decrease of Notch-1, JAG-1, and HES-1. Repression of Notch1 reversed the effect of LINC01355 in OSCC cells. In conclusion, it was implied that LINC01355 might induce the development of OSCC via modulating the Notch signal pathway, which could provide a candidate therapeutic target for OSCC.

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Blocking the regulatory T cell molecule LAG-3 augments in vivo anti-tumor immunity in an autochthonous model of prostate cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2573 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2573-2573

Author(s):

C. G. Drake ◽

C. Kelleher ◽

T. Bruno ◽

T. Harris ◽

D. Flies ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

T Cell ◽

Regulatory T Cell ◽

Specific Antigen ◽

Cell Activity ◽

Cd8 T Cell ◽

Regulatory Function

2573 Background: LAG-3 is a CD4 homolog expressed on activated T cells, NK cells, tumor infiltrating lymphocytes (TIL), and plasmacytoid dendritic cells. Recently, we showed that LAG-3 was relatively overexpressed in specific T cells rendered unresponsive in vivo by the presence of cognate self-antigen. These anergic T cells display regulatory function both in vitro and in vivo, and blockade of LAG-3 with a non-depleting monoclonal antibody significantly mitigates their regulatory T cell activity. Methods: Using a novel model of prostate cancer in which a tumor-specific antigen is expressed in autochthonous tumors, we tested whether treatment with a non-depleting anti-LAG-3 antibody affected trafficking and function of tumor-specific T cells. Results: LAG-3 blockade significantly augments specific CD8 T cell trafficking to antigen-expressing tumors, but not to normal tissue. Most significantly, LAG-3 blockade functionally reversed CD8 T cell tolerance as assayed by an in vivo cytotoxic T lymphocyte (CTL) assay. Combining LAG-3 blockade with specific anti-tumor vaccination results in a dramatic increase in activated CD8 T cells in the tumor parenchyma. Conclusions: Taken together, these data support the concept that treatment with a LAG-3 blocking antibody may significantly delay disease progression in patients with cancer. We have recently generated a panel of monoclonal antibodies directed against human LAG-3; several of these antibodies significantly augment human T cell responses in vitro. No significant financial relationships to disclose.

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Silencing of T lymphocytes by antigen-driven programmed death in recombinant adeno-associated virus vector–mediated gene therapy

Blood ◽

10.1182/blood-2008-01-131375 ◽

2009 ◽

Vol 113 (3) ◽

pp. 538-545 ◽

Cited By ~ 33

Author(s):

Victoria M. Velazquez ◽

David G. Bowen ◽

Christopher M. Walker

Keyword(s):

Gene Therapy ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Activity ◽

Cd8 T Cell ◽

Stable Gene ◽

Adeno Associated Virus ◽

Antigen Production ◽

Programmed Death

AbstractRecombinant adeno-associated virus (rAAV) vectors are considered promising for human gene replacement because they facilitate stable expression of therapeutic proteins in transduced tissues. Whether the success of gene therapy will be influenced by cellular immune responses targeting transgene-encoded proteins that are potentially immunogenic is unknown. Here we characterized CD8+ T-cell activity against β-galactosidase and enhanced green fluorescent protein, model antigens containing major histocompatibility complex (MHC) class I epitopes that are constitutively produced in murine skeletal muscle after rAAV vector transduction. Antigen-specific CD8+ T cells were detected in the spleen and liver of mice within 7 days of muscle transduction. CD8+ T-cell frequencies in these organs were stable, and effector functions were intact for months despite ongoing antigen production in muscle. CD8+ T cells also infiltrated transduced muscle, where frequencies were at least 5-fold higher than in untransduced spleen and liver. Significantly, the majority of antigen-specific CD8+ T cells in vector-transduced muscle were not functional. Loss of function in the muscle was associated with programmed death of the effector cells. Stable gene expression therefore depended on selective death of CD8+ T cells at the site of antigen production, an effective mechanism for subverting immunity that is also potentially reversible.

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Developing a screening platform for genetic and small molecule targets of cancer immunotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.66 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. 66-66

Author(s):

Ranjan Upadhyay ◽

Aleksandra Wroblewska ◽

Clara Koo ◽

Brian Brown ◽

Joshua Brody

Keyword(s):

T Cells ◽

T Cell ◽

Small Molecule ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activity ◽

Cd8 T Cell ◽

Forward Genetics ◽

Tumor Line ◽

Peptide Epitope

66 Background: The success of checkpoint blockade therapy is often dependent on CD8 T cell activation against tumor antigens. However, clinical benefit is only seen in a subset of patients, suggesting that there are other possibly targetable immunosuppressive pathways that are allowing the tumor to escape immune surveillance. Methods: A CD8 T cell that recognizes the EGFP200-208 peptide epitope allowed for the use of EGFP as a model tumor antigen while monitoring expression levels at the single cell resolution. Using a lymphoma line expressing EGFP or mCherry as our antigen-positive and -negative cancer models, we employed 3 screening strategies: 1) a forward genetics approach in which we selected for tumor cells that had naturally developed resistance to killing by CD8 T cells; 2) a reverse genetics approach that involved the use of pooled CRISPR libraries to identify knockout clones with a selection advantage or disadvantage when pressured by activated T cells; and 3) small molecule libraries, including FDA-approved drugs, to identify compounds that increased antigen-specific CD8 T cell killing. Results: Despite antigen recognition and early activation in response to the resistant tumor line, T cells failed to produce effector cytokines and underwent apoptosis in a PD-L1 and CTLA-4 independent manner. Candidate genes mediating this phenotype were derived from expression differences between the original susceptible tumor line and the immunoedited resistant tumor line. The pooled CRISPR approach was validated in a curated library by identifying genes with known roles in T cell-mediated killing and antigen presentation, such as Fas, B2m, and Tap1, as well as known suppressive molecules such as BTLA and PD-L1. LDL receptor expressed on the cancer cell emerged as a possible novel suppressor of T cells. Decitabine and 4-cinnolinethiol, among other small molecules, emerged as possible enhancers of CD8 T cell activity. Conclusions: We have identified several gene candidates as potentially novel and targetable checkpoint-like molecules, as well as small molecule compounds that may be able to enhance the anti-tumor activity of CD8 T cells. Efforts are ongoing in order to validate these targets and to screen larger libraries.

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Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of antitumor immune memory

Blood ◽

10.1182/blood-2008-11-190827 ◽

2009 ◽

Vol 113 (18) ◽

pp. 4449-4457 ◽

Cited By ~ 26

Author(s):

Weiqing Jing ◽

Jill A. Gershan ◽

Bryon D. Johnson

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Tumor Antigens ◽

Cell Activity ◽

Cd8 T Cell ◽

Immune Memory ◽

Hematopoietic Stem ◽

Immunotherapeutic Approach

Abstract High-risk neuroblastoma remains a clinically challenging disease. Here, we report that a multifaceted immunotherapeutic approach including syngeneic hematopoietic stem cell transplantation (HSCT), adoptive transfer of sensitized T cells (from syngeneic donors vaccinated to tumor antigens), and early posttransplantation tumor vaccination can effectively treat mice with established neuroblastoma. Vaccination was an important component of this immunotherapy, as it resulted in enhanced and prolonged tumor-specific CD8 T-cell activity and improved antitumor efficacy. Surprisingly, CD4 cell depletion of mice given sensitized T cells resulted in better tumor-free survival, which was associated with an early increased expansion of CD8 T cells with an effector phenotype, increased numbers of tumor-reactive CD8 T cells, and increased tumor infiltration by CD8 T cells. However, in the absence of CD4 T cells, development of long-term tumor immunity (memory) was severely compromised as reflected by diminished CD8 T-cell recall responses and an inability to resist tumor rechallenge in vivo. Based on these results, a major challenge with this immunotherapeutic approach is how to obtain the ideal initial antitumor response but still preserve antitumor immune memory. These data suggest that identification and selective depletion of immune inhibitory CD4 T cells may be a strategy to enhance early antitumor immunity and induce a long-lasting tumor response after HSCT.

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Persistent numbers of tetramer+ CD8+ T cells, but loss of interferon-γ+ HIV-specific T cells during progression to AIDS

Blood ◽

10.1182/blood.v99.7.2505 ◽

2002 ◽

Vol 99 (7) ◽

pp. 2505-2511 ◽

Cited By ~ 138

Author(s):

Stefan Kostense ◽

Kristin Vandenberghe ◽

Jeanine Joling ◽

Debbie Van Baarle ◽

Nening Nanlohy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Activity ◽

Cd8 T Cell ◽

Interferon Γ ◽

Cd4 T Cell ◽

Cytotoxic T Cell ◽

Cell Counts ◽

Ifn Γ

Although CD8+ T cells initially suppress human immunodeficiency virus (HIV) replication, cytotoxic T-cell precursor frequencies eventually decline and fail to prevent disease progression. In a longitudinal study including 16 individuals infected with HIV-1, we studied both the number and function of HIV-specific CD8+ T cells by comparing HLA-peptide tetramer staining and peptide-induced interferon-γ (IFN-γ) production. Numbers of IFN-γ–producing T cells declined during progression to acquired immunodeficiency syndrome (AIDS), whereas the number of tetramer+ T cells in many individuals persisted at high frequencies. Loss of IFN-γ–producing T cells correlated with declining CD4+ T-cell counts, consistent with the need of CD4+ T-cell help in maintaining adequate CD8+T-cell function. These data indicate that the loss of HIV-specific CD8+ T-cell activity is not due to physical depletion, but is mainly due to progressively impaired function of HIV-specific CD8+ T cells.

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451 Combining Bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) pairs local innate activation with systemic CD8+ T cell expansion to enhance anti-tumor immunity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0451 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A478-A478

Author(s):

Annah Rolig ◽

Daniel Rose ◽

Saul Kivimae ◽

Werner Rubas ◽

William Redmond

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Cd8 T Cells ◽

Cell Expansion ◽

Nk Cell ◽

Tumor Regression ◽

Cell Activity ◽

Cd8 T Cell ◽

Post Treatment

BackgroundPreviously, we demonstrated that radiation therapy (RT) combined with Bempegaldesleukin (BEMPEG;NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, led to enhanced anti-tumor efficacy through a T cell-dependent mechanism. However, we observed only modest systemic responses to BEMPEG/RT across several murine tumor models. Therefore, we explored alternative approaches to improve systemic tumor-specific immunity. We evaluated whether intratumoral NKTR-262, a polymer-modified toll-like receptor (TLR) 7/8 agonist, combined with systemic BEMPEG treatment resulted in improved tumor-specific immunity and survival compared to BEMPEG combined with RT. We hypothesized that BEMPEG/NKTR-262 immunotherapy would promote synergistic activation of local immunostimulatory innate immune responses followed by systemic adaptive immunity to significantly improve tumor regression and overall survival.MethodsTumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; iv), RT (12 Gy x 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+ and CD8+ T cell activation status in the blood and/or tumor (7 days post-treatment) and NK cell activity in the tumor (1, 3 days post-treatment). The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+ T cell activity was determined in vitro by tracking apoptosis in an Incucyte assay. Data are representative of 1–2 independent experiments (n=5–14/group) and statistical significance was determined by 1-way ANOVA (p-value cut-off of 0.05).ResultsBEMPEG/NKTR-262 resulted in significantly improved survival compared to BEMPEG/RT. BEMPEG/NKTR-262 efficacy was NK and CD8+ T cell-dependent, while BEMPEG/RT primarily relied on CD8+ T cells. Response to BEMPEG/NKTR-262 was characterized by a significant expansion of activated CD8+ T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, NKTR-262/BEMPEG induced higher frequencies of GzmA+ CD8+ T cells exhibiting reduced expression of suppressive molecules (PD-1+, TIM-3+), compared to BEMPEG/RT. Indeed, CD8+ T cells isolated from BEMPEG/NKTR-262-treated tumors had greater cytolytic capacity than those from BEMPEG/RT-treated mice. CD8+ T cell expansion (blood) and activity (tumor) depended upon the initial NK response, as neither occurred in the absence of NK cells. BEMPEG/NKTR-262 uniquely induced the expansion of early and high effector NK cells.ConclusionsCombining BEMPEG with NKTR-262 lead to an early and robust NK cell expansion not observed in the BEMPEG/RT combination. The improved tumor regression and survival was dependent on the NKTR-262 driven expansion of NK cells. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

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Anomalies of the CD8+ T cell pool in hereditary hemochromatosis: HLA-A3 linked expansions of CD28− T cells

Immunology Letters ◽

10.1016/s0165-2478(97)87757-7 ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 231

Author(s):

F Arosa

Keyword(s):

T Cells ◽

T Cell ◽

Hereditary Hemochromatosis ◽

Cd8 T Cell ◽

Cell Pool

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