Contact-dependent killing by cytotoxic T lymphocytes is insufficient for EL4 tumor regression in vivo

Beck, R.J.; Slagter, M.; Beltman, J.B. (2019)

Article / Letter to editor

Immunotherapies are an emerging strategy for treatment of solid tumors. Improved understanding of the mechanisms employed by cytotoxic T lymphocytes (CTLs) 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 (ODE) model of tumor regression after adoptive transfer of a population of CTLs. Models were parameterized based on in vivo 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 in vivo was insufficient to cause tumor regression. In our ABM we also simulated CTL production of the cytokine interferon gamma (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 to direct killing alone. Collectively these data demonstrate that contact-dependent killing is insufficient for EL4 regression in vivo and highlight the potential importance of cytokine-induced antiproliferative effects in T cell-mediated tumor control.

• Agent Based Model
• Differential Equation Model
• Immune responses to cancer
• CTL-mediated target cell killing
• IFNγ-induced cell cycle arrest

• All authors: Beck, R.J.; Slagter, M.; Beltman, J.B.
• Date: 2019-04-30
• Journal: Cancer Research
• Volume: 79
• Issue: 13
• Pages: 3406 - 3416
• DOI: doi:10.1158/0008-5472.CAN-18-3147