scholarly journals Induction of Potent CD8 T Cell Cytotoxicity by Specific Targeting of Antigen to Cross-Presenting Dendritic Cells In Vivo via Murine or Human XCR1

2014 ◽  
Vol 194 (3) ◽  
pp. 1069-1079 ◽  
Author(s):  
Evelyn Hartung ◽  
Martina Becker ◽  
Annabell Bachem ◽  
Nele Reeg ◽  
Anika Jäkel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cell Cytotoxicity ◽  
Specific Targeting ◽  
T Cell Cytotoxicity

scholarly journals PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity

2017 ◽  
Vol 214 (4) ◽  
pp. 895-904 ◽  
Author(s):  
Vikram R. Juneja ◽  
Kathleen A. McGuire ◽  
Robert T. Manguso ◽  
Martin W. LaFleur ◽  
Natalie Collins ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Antitumor Immunity ◽  
Cd8 T Cell ◽  
Genetically Engineered ◽  
Mouse Tumor ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

It is unclear whether PD-L1 on tumor cells is sufficient for tumor immune evasion or simply correlates with an inflamed tumor microenvironment. We used three mouse tumor models sensitive to PD-1 blockade to evaluate the significance of PD-L1 on tumor versus nontumor cells. PD-L1 on nontumor cells is critical for inhibiting antitumor immunity in B16 melanoma and a genetically engineered melanoma. In contrast, PD-L1 on MC38 colorectal adenocarcinoma cells is sufficient to suppress antitumor immunity, as deletion of PD-L1 on highly immunogenic MC38 tumor cells allows effective antitumor immunity. MC38-derived PD-L1 potently inhibited CD8+ T cell cytotoxicity. Wild-type MC38 cells outcompeted PD-L1–deleted MC38 cells in vivo, demonstrating tumor PD-L1 confers a selective advantage. Thus, both tumor- and host-derived PD-L1 can play critical roles in immunosuppression. Differences in tumor immunogenicity appear to underlie their relative importance. Our findings establish reduced cytotoxicity as a key mechanism by which tumor PD-L1 suppresses antitumor immunity and demonstrate that tumor PD-L1 is not just a marker of suppressed antitumor immunity.

scholarly journals Antigen Presented by Tumors In vivo Determines the Nature of CD8+ T-Cell Cytotoxicity

2009 ◽  
Vol 69 (16) ◽  
pp. 6615-6623 ◽  
Author(s):  
Anil Shanker ◽  
Alan D. Brooks ◽  
Kristen M. Jacobsen ◽  
John W. Wine ◽  
Robert H. Wiltrout ◽  
...  
Keyword(s):  
T Cell ◽  
Cd8 T Cell ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

scholarly journals Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-  signals in vivo

2004 ◽  
Vol 102 (2) ◽  
pp. 419-424 ◽  
Author(s):  
M.-L. Chen ◽  
M. J. Pittet ◽  
L. Gorelik ◽  
R. A. Flavell ◽  
R. Weissleder ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cell ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

851 Potent tumor-directed T cell activation and in vivo tumor inhibition induced by a 4–1BB x 5T4 ADAPTIR™ bispecific antibody

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A904-A904
Author(s):  
Michelle Nelson ◽  
Robert Miller ◽  
Anneli Nilsson ◽  
Lill Ljung ◽  
Allison Chunyk ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Tumor Cell ◽  
Bispecific Antibody ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Cell Tumor ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

Background4-1BB (CD137) is an activation-induced co-stimulatory receptor that regulates immune responses of activated CD8+ T cells and NK cells, by enhancing proliferation, survival, cytolytic activity and IFN-γ production. Its ability to induce potent anti-tumor CD8+ and NK cell activity makes 4-1BB an attractive target for designing novel therapeutics for immuno-oncology. However, clinical development of a monospecific 4-1BB agonistic antibody has been hampered by dose-limiting hepatic toxicities. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel 4-1BB x 5T4 bispecific antibody that stimulates 4-1BB function only when co-engaged with 5T4, a tumor-associated antigen. The combined preclinical dataset presented here provides an overview of the mechanism of action and the efficacy and safety profile of ALG.APV-527, supporting its advancement into the clinic.MethodsALG. APV-527 was built based the ADAPTIR™ platform with binding domains to 4-1BB and 5T4 generated using the ALLIGATOR-GOLD® human scFv library. ALG.APV-527 was tested using primary cells in the presence or absence of cells expressing 5T4. Cell Trace-labelled PBMC sub-optimally stimulated with anti-CD3, to induce 4-1BB expression, cells were gated using flow cytometry. T cell cytotoxicity was assessed by quantifying cell death in CD8+ T cell/tumor cell co-cultures, and images were obtained using a cell live imaging system (Cytation 5). For tumor inhibition studies, human 4-1BB knock-in mice were injected subcutaneously with MB49 cells transfected with human 5T4. Cured mice were subsequently used in a toxicity study and liver pathology was evaluated.ResultsIn vitro, ALG.APV-527 enhances primary CD8+ T cell and NK cell function and proliferation in the presence of 5T4-expressing cells. Using imaging, ALG.APV-527 in combination with a bispecific T cell engager caused increased cell death in T cell/tumor cell co-cultures. ALG.APV-527 inhibited growth of established tumors at doses as low as 2 µg/mouse in a syngeneic bladder cancer model. Following recovery, mice exhibited a memory response when rechallenged with tumor. In a high dose safety study in human 4-1BB knock-in mice, ALG.APV-527 did not cause significant systemic immune activation, whereas urelumab analogue treated mice induced dermatitis, elevated serum cytokines, CD8+ T-cell liver infiltration and systemic T-cell proliferation.ConclusionsALG. APV-527 induces potent CD8+ T cell and NK cell co-stimulation and T-cell cytotoxicity and has potent in vivo anti-tumor activity, without inducing systemic toxicity. Based on preclinical data, ALG.APV-527 is a promising anti-cancer therapeutic for the treatment of a variety of 5T4-expressing solid tumors.Ethics ApprovalAll studies were review and approved by the Internal Animal Care and Use Committee (IACUC) of Aptevo Therapeutics

A Method to Evaluate In Vivo CD8+ T Cell Cytotoxicity in a Murine Model

2020 ◽  
pp. 549-558
Author(s):  
Felicity C. Stark ◽  
Renu Dudani ◽  
Gerard Agbayani ◽  
Michael J. McCluskie
Keyword(s):  
T Cell ◽  
Murine Model ◽  
Cd8 T Cell ◽  
Cell Cytotoxicity ◽  
T Cell Cytotoxicity

scholarly journals Ganglioside Inhibition of CD8+T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

2012 ◽  
Vol 189 (7) ◽  
pp. 3521-3527 ◽  
Author(s):  
Hee Chul Lee ◽  
Assefa Wondimu ◽  
Yihui Liu ◽  
Jennifer S. Y. Ma ◽  
Saša Radoja ◽  
...  
Keyword(s):  
T Cell ◽  
Cd8 T Cell ◽  
Cell Cytotoxicity ◽  
Lytic Granule ◽  
T Cell Cytotoxicity
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