Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge.
Immune-mediated regression of established B16F10 melanoma by intratumoral injection of attenuated Toxoplasma gondii protects against rechallenge.
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DOI：
10.4049/jimmunol.1201209
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Fiering S
中科院分区：
文献类型：
--
作者：
Baird JR;Byrne KT;Lizotte PH;Toraya-Brown S;Scarlett UK;Alexander MP;Sheen MR;Fox BA;Bzik DJ;Bosenberg M;Mullins DW;Turk MJ;Fiering S
肿瘤的免疫识别可以限制癌症的发展，但抗肿瘤免疫应答通常被肿瘤介导的免疫抑制所阻断。由于微生物或微生物成分是刺激免疫应答的强大佐剂，我们评估了高度免疫原性但减毒的寄生虫的瘤内给药是否可以诱导对已建立的免疫原性差的肿瘤的排斥。我们通过瘤内注射弓形虫减毒株（cps）治疗皮内B16 F10小鼠黑色素瘤，弓形虫减毒株不能在体内复制，因此不具有感染性。cps治疗在体内刺激了强烈的CD 8 + T细胞介导的抗肿瘤免疫应答，使已建立的原发性黑色素瘤消退。cps单一疗法迅速改变了肿瘤微环境，停止了肿瘤生长，随后，随着肿瘤反应性T细胞的扩增，肿瘤消失，很少复发。治疗需要可以侵入细胞的活cps，还需要CD 8 + T细胞和自然杀伤细胞，但不需要CD 4 + T细胞。此外，我们证明了IL-12、IFN-γ和CXCR 3刺激细胞因子是完全治疗功效所需的。该治疗产生了全身抗肿瘤免疫活性以及抗肿瘤免疫记忆，因此可能对人类转移性疾病产生影响。该方法对B16 F10或黑色素瘤都没有特异性。直接瘤内注射cps对诱导型遗传性黑色素瘤模型、可移植性肺肿瘤和卵巢肿瘤有效，显示了广泛的临床应用潜力。有效性、全身抗肿瘤免疫应答和完全减毒且未观察到宿主毒性的组合证明了这种新型癌症疗法的潜在价值。
Immune recognition of tumors can limit cancer development, but antitumor immune responses are often blocked by tumor-mediated immunosuppression. Since 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. cps treatment stimulated a strong CD8+ T cell-mediated antitumor immune response in vivo that regressed established primary melanoma. 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 Natural Killer cells but did not require CD4+ T cells. Furthermore, we demonstrate that IL-12, IFN-γ 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.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.1158/1078-0432.ccr-11-0503
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Klebanoff CA;Gattinoni L;Palmer DC;Muranski P;Ji Y;Hinrichs CS;Borman ZA;Kerkar SP;Scott CD;Finkelstein SE;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
影响因子：
11.2
作者：
Manuel ER;Blache CA;Paquette R;Kaltcheva TI;Ishizaki H;Ellenhorn JD;Hensel M;Metelitsa L;Diamond DJ
通讯作者：
Diamond DJ
影响因子：
3.1
作者：
GROSS, U;MULLER, WA;HEESEMANN, J
通讯作者：
HEESEMANN, J
影响因子：
7.8
作者：
Paterson Y;Guirnalda PD;Wood LM
通讯作者：
Wood LM