Immune-Mediated Regression of Established B16F10 Melanoma by Intratumoral Injection of Attenuated Toxoplasma gondii Protects against Rechallenge

被引:104
作者
Baird, Jason R. [1 ]
Byrne, Katelyn T. [1 ]
Lizotte, Patrick H. [1 ]
Toraya-Brown, Seiko [1 ]
Scarlett, Uciane K. [1 ]
Alexander, Matthew P. [1 ]
Sheen, Mee Rie [1 ]
Fox, Barbara A. [1 ]
Bzik, David J. [1 ]
Bosenberg, Marcus [2 ,3 ]
Mullins, David W. [1 ,4 ]
Turk, Mary Jo [1 ,4 ]
Fiering, Steven [1 ,4 ,5 ]
机构
[1] Dartmouth Med Sch, Dept Microbiol & Immunol, Hanover, NH 03755 USA
[2] Yale Univ, Dept Dermatol, New Haven, CT 06520 USA
[3] Yale Univ, Dept Pathol, New Haven, CT 06520 USA
[4] Norris Cotton Canc Ctr, Lebanon, NH 03756 USA
[5] Dartmouth Med Sch, Dept Genet, Hanover, NH 03755 USA
基金
美国国家卫生研究院;
关键词
T-CELL RESPONSES; LISTERIA-MONOCYTOGENES; METASTATIC MELANOMA; CHRONIC INFECTION; CANCER VACCINE; BREAST-TUMORS; STAGE-III; MICE; RESISTANCE; GROWTH;
D O I
10.4049/jimmunol.1201209
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
071005 [微生物学]; 100108 [医学免疫学];
摘要
Immune recognition of tumors can limit cancer development, but antitumor immune responses are often blocked by tumor-mediated immunosuppression. Because microbes or microbial constituents are powerful adjuvants to stimulate immune responses, we evaluated whether intratumoral administration of a highly immunogenic but attenuated parasite could induce rejection of an established poorly immunogenic tumor. We treated intradermal B16F10 murine melanoma by intratumoral injection of an attenuated strain of Toxoplasma gondii (cps) that cannot replicate in vivo and therefore is not infective. The cps treatment stimulated a strong CD8(+) T cell-mediated antitumor immune response in vivo that regressed established primary melanoma. The cps monotherapy rapidly modified the tumor microenvironment, halting tumor growth, and subsequently, as tumor-reactive T cells expanded, the tumors disappeared and rarely returned. The treatment required live cps that could invade cells and also required CD8(+) T cells and NK cells, but did not require CD4(+) T cells. Furthermore, we demonstrate that IL-12, IFN-gamma, and the CXCR3-stimulating cytokines are required for full treatment efficacy. The treatment developed systemic antitumor immune activity as well as antitumor immune memory and therefore might have an impact against human metastatic disease. The approach is not specific for either B16F10 or melanoma. Direct intratumoral injection of cps has efficacy against an inducible genetic melanoma model and transplantable lung and ovarian tumors, demonstrating potential for broad clinical use. The combination of efficacy, systemic antitumor immune response, and complete attenuation with no observed host toxicity demonstrates the potential value of this novel cancer therapy. The Journal of Immunology, 2013, 190: 469-478.
引用
收藏
页码:469 / 478
页数:10
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