Abstract
Cryoablation of a solitary tumor mass releases intact tumor antigens and can induce protective antitumor immunity but has limited efficacy in the treatment of established metastatic cancer. Cyclophosphamide (Cy), an anticancer drug, selectively depletes regulatory T cells (Tregs) and attenuates suppression of antitumor immunity. We used a BALB/c mouse model of metastatic colon cancer to investigate the systemic antitumor effects of in situ cryotherapy alone or in combination with 200 mg/kg i.p. Cy. When combined with Cy, cryoablation was significantly more effective than either surgical excision or cautery at inducing systemic antitumor immunity, resulting in the cure of a fraction of animals with established metastatic disease and resistance to tumor rechallenge. Lymphocytes from cured animals contained an expanded population of tumor-specific, interferon-γ producing T cells and transferred antitumor immunity to naive recipients. Depletion of CD8+ cells significantly impaired the adoptive transfer of antitumor immunity. Furthermore, treatment with Cy and cryoablation was associated with a significant decrease in the ratio of regulatory to effector CD4+ T cells. The combination of tumor cryoablation and Cy induces potent, systemic antitumor immunity in animals with established metastatic disease.
Footnotes
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This work was supported in part by the National Institutes of Health [Grants R01-CA105148, P01-CA15396]; and the Patrick C. Walsh Prostate Cancer Research Fund.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.152603.
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ABBREVIATIONS: Treg, regulatory T cell; NK, natural killer; Cy, cyclophosphamide; MST, median survival time; HR, hazard ratio; CI, confidence interval; CTL, cytotoxic T lymphocyte.
- Received February 23, 2009.
- Accepted April 29, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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