Figure 6. Increased MTD and anticancer effects in Tnfrsf1a^+/– mice.

Antitumor effect and survival after 10 days of high-dose TNF (50 μg/mouse) plus IFN-γ treatment (5,000 IU). (A) Toxicity of TNF plus IFN-γ in Tnfrsf1a^+/+ mice (black triangles) and Tnfrsf1a^+/– mice (blue circles). Healthy tumor-free mice (continuous line) and B16BL6 melanoma-bearing mice (dotted line) were injected daily with different doses of TNF plus IFN-γ for 10 days. Healthy mice were injected i.p., whereas tumor-bearing mice were injected s.c. paralesional. The horizontal line represents LD₅₀. (B) B16BL6 melanoma-bearing Tnfrsf1a^+/+, Tnfrsf1a^+/–, and Tnfrsf1a^–/– mice were treated daily by paralesional s.c. injection with PBS (white symbols; Tnfrsf1a^+/+, n = 5; Tnfrsf1a^+/–, n = 3; Tnfrsf1a^–/–, n = 4) or high-dose TNF (black symbols; Tnfrsf1a^+/+, n = 6; Tnfrsf1a^+/–, n = 10; Tnfrsf1a^–/–, n = 6) plus IFN-γ. Tnfrsf1a^–/– mice had to be euthanized due to large tumor size (indicated by //). (C) LLC-bearing mice were treated daily with PBS (white symbols; Tnfrsf1a^+/+, n = 6; Tnfrsf1a^+/–, n = 9; Tnfrsf1a^–/–, n = 4) or TNF/IFN-γ (black symbols; Tnfrsf1a^+/+, n = 5; Tnfrsf1a^+/–, n = 13; Tnfrsf1a^–/–, n = 9). (D) B16BL6 melanoma-bearing Tnfrsf1a^fl/fl and Villin-Cre Tnfrsf1a^fl/fl mice were treated daily by paralesional injection of 12 mg TNF plus IFN-γ (5,000 IU) for 10 days (Tnfrsf1a^fl/fl, n = 20 and Villin-Cre Tnfrsf1a^fl/fl, n = 16). Tnfrsf1a^fl/fl PBS-treated mice (n = 11) had to be euthanized because of their large tumor size (indicated by //). Data represent mean ± SEM. *P < 0.05, ***P < 0.001, Student’s t test in B and C (left) and log-rank test (right); in tumor size index (TSI) graphs, compared with PBS- and TNF/IFN-γ–treated Tnfrsf1a^+/– (A–C) or TNF/IFN-γ–treated Tnfrsf1a^fl/fl and Villin-Cre Tnfrsf1a^fl/fl (D).