Abstract
Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC) tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum) levels of proinflammatory cytokines. In conclusion, imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for imidazoquinoline in RCC.
Highlights
Kidney cancer is responsible annually for over 58,000 new diagnoses and 13,000 deaths in the US [1]
renal cell carcinoma (RCC) solid tumors are highly immunogenic with abundant Tcell lymphocytic infiltration, and immunotherapies such as IL-2 and IFN-alpha are among the most successful systemic treatments for RCC patients [7, 8]
Only a minority of metastatic RCC patients respond to these treatments, and primary tumors are resistant, suggestive of underlying RCC immunoevasion
Summary
Kidney cancer is responsible annually for over 58,000 new diagnoses and 13,000 deaths in the US [1]. 85% of these cancers are renal cell carcinomas (RCCs) arising from the renal tubule epithelial lining. Despite earlier stage of detection in recent decades, RCC patient mortality has not decreased and recurrence following definitive local therapy by surgery or ablative techniques remains a significant clinical challenge [2]. For patients presenting or recurring with RCC metastases, prognosis is poor, with a 5-year survival of less than 10% [3]. While multityrosine kinase inhibitors have shown recent promise with frequent clinical responses, complete responders are lacking, and there is question regarding survival benefits and durability of response [4, 5]
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