BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.
BCG invokes superior STING-mediated innate immune response over radiotherapy in a carcinogen murine model of urothelial cancer.
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BCG在尿路上皮癌的致癌鼠模型中引用了刺激性介导的先天免疫反应而不是放射疗法。
DOI：
10.1002/path.5830
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Bivalacqua TJ
中科院分区：
文献类型：
--
作者：
Lombardo KA;Obradovic A;Singh AK;Liu JL;Joice G;Kates M;Bishai W;McConkey D;Chaux A;Eich ML;Rezaei MK;Netto GJ;Drake CG;Tran P;Matoso A;Bivalacqua TJ
Radiation and Bacillus Calmette-Guérin (BCG) instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response however comparison of STING-pathway molecules and immune landscape following treatment in urothelial carcinoma has not be performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15Gy dose of radiation or 3 intravesical instillations of BCG (1×108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using the NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation.
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影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
3.3
作者：
Eich, Marie-Lisa;Chaux, Alcides;Netto, George J.
通讯作者：
Netto, George J.
影响因子：
10.1
作者：
Kates, Max;Nirschl, Thomas;Bivalacqua, Trinity J.
通讯作者：
Bivalacqua, Trinity J.
影响因子：
1.1
作者：
Koti, Madhuri;Chenard, Stephen;Siemens, D. Robert
通讯作者：
Siemens, D. Robert