Abstract
BackgroundCurrent therapies for advanced renal cell carcinoma (RCC) have low cure rates or significant side effects. It has been reported that complexes composed of interleukin (IL)-2 and stimulating anti-IL-2 antibody (IL-2C) suppress malignant melanoma growth. We investigated whether it could have similar effects on RCC.MethodsA syngeneic RCC model was established by subcutaneously injecting RENCA cells into BALB/c mice, which were administered IL-2C or phosphate-buffered saline every other day for 4 weeks. RCC size was measured serially, and its weight was assessed 4 weeks after RENCA injection. Immune cell infiltration into RCC lesions and spleen was assessed by flow cytometry and immunohistochemistry.ResultsIL-2C treatment increased the numbers of CD8+ memory T and natural killer (NK) cells in healthy BALB/c mice (P < 0.01). In the spleen of RCC mice, IL-2C treatment also increased the number of CD8+ memory T, NK cells, and macrophages as compared to PBS-treated controls (P < 0.01). The number of interferon-γ- and IL-10-producing splenocytes increased and decreased, respectively after 4 weeks in the IL-2C-treated mice (P < 0.01). Tumor-infiltrating immune cells including CD4+ T, CD8+ T, NK cells as well as macrophages were increased in IL-2C-treated mice than controls (P < 0.05). Pulmonary edema, the most serious side effect of IL-2 therapy, was not exacerbated by IL-2C treatment. However, IL-2C had insignificant inhibitory effect on RCC growth (P = 0.1756).ConclusionsIL-2C enhanced immune response without significant side effects; however, this activity was not sufficient to inhibit RCC growth in a syngeneic, murine model.
Highlights
Current therapies for advanced renal cell carcinoma (RCC) have low cure rates or significant side effects
These results suggest that Complex of interleukin-2 and stimulating anti-IL-2 antibody (IL-2C) treatment can enhance anti-tumor immunity
Among RCC mice, there was no difference in the number of CD4+ T cells between the IL-2C and phosphatebuffered saline (PBS) groups (Fig. 2a; P = 0.498)
Summary
Current therapies for advanced renal cell carcinoma (RCC) have low cure rates or significant side effects. It has been reported that complexes composed of interleukin (IL)-2 and stimulating anti-IL-2 antibody (IL-2C) suppress malignant melanoma growth. We investigated whether it could have similar effects on RCC. RCC is considered as an immunogenic tumor owing to its spontaneous regression, variable growth, late metastasis, high degree of T cell infiltration, and high incidence in immunosuppressed patients. Blockade of CTLA4, a T-cell inhibitory receptor with ipilimumab, and increasing T-cell proliferation and cytotoxic effects with PD-1/PD-L1 axis inhibition induced regression of renal cell carcinoma in some patients [15, 16]. High-dose IL-2 therapy induces systemic inflammatory responses, including capillary leak syndrome, heart failure, and pulmonary edema, thereby hindering the broad application of high-dose IL-2 therapy in the treatment of advanced RCC [17, 18]
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