A uracil auxotroph Toxoplasma gondii exerting immunomodulation to inhibit breast cancer growth and metastasis.
A uracil auxotroph Toxoplasma gondii exerting immunomodulation to inhibit breast cancer growth and metastasis.
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尿嘧啶营养缺陷型弓形虫通过免疫调节抑制乳腺癌生长和转移
DOI：
10.1186/s13071-021-05032-6
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发表时间：
2021-12-11
影响因子：
3.2
通讯作者：
Peng HJ
中科院分区：
文献类型：
--
作者：
Xu LQ;Yao LJ;Jiang D;Zhou LJ;Chen M;Liao WZ;Zou WH;Peng HJ
乳腺癌是女性癌症相关死亡的最常见原因，三阴性乳腺癌（TNBC）患者的预后尤其差；因此，迫切需要新的有效治疗方法。最近的研究表明，尿嘧啶缺乏型刚地弓形虫疫苗具有抗肿瘤作用。在这里，我们研究了一种减毒的尿嘧啶缺陷型弓形虫菌株对4T1小鼠乳腺癌的免疫治疗效果。我们利用CRISPR/Cas9技术，通过orotidine 5 ' -单磷酸脱羧酶基因缺失（RH-Δompdc）构建了一株尿嘧啶缺乏性弓形虫RH菌株。通过寄生虫复制试验、斑块试验、小鼠腹膜液寄生虫负荷检测和生存分析，测定该菌株在弓形虫感染小鼠体内和体外的毒力。通过细胞因子检测评价菌株的免疫调节能力。用小鼠模型原位接种4T1肿瘤，评价其抗肿瘤作用；测定肿瘤体积，苏木精、伊红及Ki67抗体染色检测4T1肺转移，酶联免疫吸附法检测细胞因子水平。RH-Δompdc菌株在添加尿嘧啶时增殖正常，但在不添加尿嘧啶和体内不能繁殖，提示其对宿主无毒。该突变体表现出疫苗特性，可以通过显著提高炎症细胞因子的表达，在体外和体内诱导强烈的免疫反应。在4T1肿瘤中原位接种RH-Δompdc可抑制肿瘤生长，减少肺转移，促进荷瘤小鼠的生存，并增加血清和肿瘤微环境（TME）中Th1细胞因子的分泌，包括白细胞介素-12 （IL-12）和干扰素-γ (INF-δ)。在4T1肿瘤中直接接种尿嘧啶营养不良RH-Δompdc，可刺激小鼠抗感染和抗肿瘤免疫，抑制肿瘤生长和转移，促进荷瘤小鼠存活，增加血清和TME中IL-12和IFN-γ的分泌。我们的研究结果表明RH-Δompdc引起的免疫调节可能是一种潜在的抗肿瘤策略。在线版本包含补充材料，可在10.1186/s13071-021-05032-6获得。
Breast cancer is the most common cause of cancer-related death among women, and prognosis is especially poor for patients with triple-negative breast cancer (TNBC); therefore, there is an urgent need for new effective therapies. Recent studies have demonstrated that the uracil auxotroph Toxoplasma gondii vaccine displays anti-tumor effects. Here, we examined the immunotherapy effects of an attenuated uracil auxotroph strain of T. gondii against 4T1 murine breast cancer. We constructed a uracil auxotroph T. gondii RH strain via orotidine 5′-monophosphate decarboxylase gene deletion (RH-Δompdc) with CRISPR/Cas9 technology. The strain’s virulence in the T. gondii-infected mice was determined in vitro and in vivo by parasite replication assay, plaque assay, parasite burden detection in mice peritoneal fluids and survival analysis. The immunomodulation ability of the strain was evaluated by cytokine detection. Its anti-tumor effect was evaluated after its in situ inoculation into 4T1 tumors in a mouse model; the tumor volume was measured, and the 4T1 lung metastasis was detected by hematoxylin and eosin and Ki67 antibody staining, and the cytokine levels were measured by an enzyme-linked immunosorbent assay. The RH-Δompdc strain proliferated normally when supplemented with uracil, but it was unable to propagate without the addition of uracil and in vivo, which suggested that it was avirulent to the hosts. This mutant showed vaccine characteristics that could induce intense immune responses both in vitro and in vivo by significantly boosting the expression of inflammatory cytokines. Inoculation of RH-Δompdc in situ into the 4T1 tumor inhibited tumor growth, reduced lung metastasis, promoted the survival of the tumor-bearing mice and increased the secretion of Th1 cytokines, including interleukin-12 (IL-12) and interferon-γ (INF-δ), in both the serum and tumor microenvironment (TME). Inoculation of the uracil auxotroph RH-Δompdc directly into the 4T1 tumor stimulated anti-infection and anti-tumor immunity in mice, and resulted in inhibition of tumor growth and metastasis, promotion of the survival of the tumor-bearing mice and increased secretion of IL-12 and IFN-γ in both the serum and TME. Our findings suggest that the immunomodulation caused by RH-Δompdc could be a potential anti-tumor strategy. The online version contains supplementary material available at 10.1186/s13071-021-05032-6.
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DOI：
10.1073/pnas.1801910115
发表时间：
2018-08-07
影响因子：
11.1
作者：
Deng W;Lira V;Hudson TE;Lemmens EE;Hanson WG;Flores R;Barajas G;Katibah GE;Desbien AL;Lauer P;Leong ML;Portnoy DA;Dubensky TW Jr
通讯作者：
Dubensky TW Jr
DOI：
10.4049/jimmunol.1201209
发表时间：
2013-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
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
通讯作者：
Fiering S
影响因子：
9.6
作者：
Fox BA;Sanders KL;Chen S;Bzik DJ
通讯作者：
Bzik DJ
DOI：
10.1111/j.1365-2613.2007.00539.x
发表时间：
2007-10-01
影响因子：
3
作者：
DuPre, Sally A.;Redelman, Doug;Hunter, Kenneth W., Jr.
通讯作者：
Hunter, Kenneth W., Jr.
DOI：
10.6004/jnccn.2016.0037
发表时间：
2016-03-01
影响因子：
13.4
作者：
Gradishar, William J.;Anderson, Benjamin O.;Kumar, Rashmi
通讯作者：
Kumar, Rashmi