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Stimulation through CD40 on Mouse and Human Renal Cell Carcinomas Triggers Cytokine Production, Leukocyte Recruitment, and Antitumor Responses that Can Be Independent of Host CD40 Expression^1,2

Lynnette Shorts^*, Jonathan M. Weiss^*, Jong-Keuk Lee, Lisbeth A. Welniak, Jeffrey Subleski^*, Timothy Back, William J. Murphy and Robert H. Wiltrout^3,*

^* Laboratory of Experimental Immunology and Intramural Research Support Program, SAIC-Frederick, Nactional Cancer Institute Center For Cancer Research, Frederick MD 21702-1201; National Genome Research Institute, National Institutes of Health, 5 Nokbun-dong, Eunpyung-ku, Seoul 122-701, Korea; and Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV 89557

CD40, a member of the TNFR superfamily, is expressed on a variety of host immune cells, as well as some tumors. In this study, we show that stimulation of CD40 expressed on both mouse and human renal carcinoma cells (RCCs) triggers biological effects in vitro and in vivo. Treatment of the CD40⁺ Renca mouse RCC tumor cells in vitro with an agonistic anti-CD40 Ab induced strong expression of the genes and proteins for GM-CSF and MCP-1, and induced potent chemotactic activity. Similarly, administration of CD40 to both wild-type and CD40^–/– mice bearing Renca tumors resulted in substantial amounts of TNF- and MCP-1 in the serum, increased the number of total splenocytes and MHC class II⁺ CD11c⁺ leukocytes, and when combined with IFN-, inhibited the progression of established Renca tumors in vivo in both wild-type and CD40^–/– mice. Similarly, treatment of CD40⁺ A704 and ACHN human RCC lines with mouse anti-human CD40 Ab induced strong expression of genes and proteins for MCP-1, IL-8, and GM-CSF in vitro and in vivo. Finally, in SCID mice, the numbers of ACHN pulmonary metastases were dramatically reduced by treatment with species-specific human CD40 Ab. These results show that CD40 stimulation of CD40⁺ tumor cells can enhance immune responses and result in antitumor activity.