Tumor necrosis factor alpha mediates the antitumor effect of combined interleukin-2 and whole body hyperthermia

Combined whole body hyperthermia (WBHT) and interleukin-2 (IL-2) significantly reduces the growth rate of subcutaneous 10 day MCA-105 tumors in C57BL/6 mice, but not in 3-day tumors. Others have shown that macroscopic tumors show reduced growth with tumor necrosis factor alpha (TNF alpha) therapy compared with microscopic tumors. We sought to determine if the antitumor effect of combined WBHT+IL-2 is mediated by TNF alpha. After inducing MCA-105 sarcoma in the right hind limb on Day 0, C57BL/6 mice were randomized to treatment groups (six each) on Day 10: control, WBHT alone, IL-2 alone, and WBHT+IL-2. Pooled serum was assessed by ELISA for TNF alpha level: control (350 pg/ml), WBHT (250 pg/ml), IL-2 alone (>2450 pg/ml), and WBHT+IL-2 (>2450 pg/ml). Using the same tumor model, animals were treated in the following groups: control, WBHT+IL-2, anti-TNF alpha Ab alone, and WBHT+IL-2+Ab. Mice in the control, Ab alone, and WBHT+IL-2+Ab groups had similar tumor growth rates (P > 0.05). However, the growth rate for WBHT+IL-2 was significantly lower (P < 0.05) compared to the other three groups. These data demonstrate significantly increased TNF alpha levels in mice treated with combined therapy and abrogation of the antitumor effect of WBHT+IL-2 therapy by the addition of anti-TNF alpha Ab with a tumor growth rate similar to that observed in untreated mice, suggesting that the antitumor effect of WBHT+IL-2 is mediated at least in part by TNF alpha.