Contact-Dependent Killing by Cytotoxic T Lymphocytes Is Insufficient for EL4 Tumor Regression In Vivo

Immunotherapies are an emerging strategy for treatment of solid tumors. Improved understanding of the mechanisms employed by cytotoxic T lymphocytes (CTL) to control tumors will aid in the development of immunotherapies. CTLs can directly kill tumor cells in a contact-dependent manner or may exert i...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Jg. 79; H. 13; S. 3406
Hauptverfasser: Beck, Richard J, Slagter, Maarten, Beltman, Joost B
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.07.2019
Schlagworte:
Adoptive Transfer
Animals
Cell Movement
Cell Proliferation
Cytokines - metabolism
Cytotoxicity, Immunologic - immunology
Lymphocyte Activation - immunology
Mice
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
Thymoma - immunology
Thymoma - metabolism
Thymoma - pathology
Thymoma - therapy
Thymus Neoplasms - immunology
Thymus Neoplasms - metabolism
Thymus Neoplasms - pathology
Thymus Neoplasms - therapy
Tumor Cells, Cultured
ISSN:1538-7445, 1538-7445
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Zusammenfassung:Immunotherapies are an emerging strategy for treatment of solid tumors. Improved understanding of the mechanisms employed by cytotoxic T lymphocytes (CTL) to control tumors will aid in the development of immunotherapies. CTLs can directly kill tumor cells in a contact-dependent manner or may exert indirect effects on tumor cells via secretion of cytokines. Here, we aim to quantify the importance of these mechanisms in murine thymoma EL4/EG7 cells. We developed an agent-based model (ABM) and an ordinary differential equation model of tumor regression after adoptive transfer of a population of CTLs. Models were parameterized based on measurements of CTL infiltration and killing rates applied to EL4/EG7 tumors and OTI T cells. We quantified whether infiltrating CTLs are capable of controlling tumors through only direct, contact-dependent killing. Both models agreed that the low measured killing rate of CTLs was insufficient to cause tumor regression. In our ABM, we also simulated CTL production of the cytokine IFNγ in order to explore how an antiproliferative effect of IFNγ might aid CTLs in tumor control. In this model, IFNγ substantially reduced tumor growth compared with direct killing alone. Collectively, these data demonstrate that contact-dependent killing is insufficient for EL4 regression and highlight the potential importance of cytokine-induced antiproliferative effects in T-cell-mediated tumor control. SIGNIFICANCE: Computational modeling highlights the importance of cytokine-induced antiproliferative effects in T-cell-mediated control of tumor progression.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-18-3147