Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer.
Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer.
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DOI：
10.1136/jitc-2021-004191
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Zitvogel L
中科院分区：
文献类型：
--
作者：
Terrisse S;Goubet AG;Ueda K;Thomas AM;Quiniou V;Thelemaque C;Dunsmore G;Clave E;Gamat-Huber M;Yonekura S;Ferrere G;Rauber C;Pham HP;Fahrner JE;Pizzato E;Ly P;Fidelle M;Mazzenga M;Costa Silva CA;Armanini F;Pinto F;Asnicar F;Daillère R;Derosa L;Richard C;Blanchard P;Routy B;Culine S;Opolon P;Silvin A;Ginhoux F;Toubert A;Segata N;McNeel DG;Fizazi K;Kroemer G;Zitvogel L
前列腺癌 (PC) 对雄激素剥夺疗法 (ADT) 的反应通常是短暂的，从激素敏感型 PC (HSPC) 发展为去势抵抗型 PC (CRPC)。我们研究了 PC 小鼠模型以及 PC 患者的标本，以揭示胸腺来源的 T 淋巴细胞和肠道微生物群对 ADT 功效的意想不到的贡献。临床前实验在免疫功能正常或免疫缺陷的携带 PC 的小鼠中进行。与此同时，我们前瞻性地纳入了 65 名 HSPC 和 CRPC 患者（Oncobiotic 试验）来分析他们的粪便和血液样本。在携带 PC 的小鼠中，ADT 增加了胸腺细胞结构和输出。与免疫功能正常的小鼠相比，植入T淋巴细胞耗尽或无胸腺的小鼠中的PC对ADT的反应效率较低。此外，口服抗生素消耗肠道微生物群会降低 ADT 的疗效。 PC 降低了肠道中 Akkermansia muciniphila 的相对丰度，而 ADT 可以逆转这种效应。此外，将携带 PC 的小鼠与无肿瘤小鼠共同饲养或口服阿克曼氏菌可提高 ADT 的疗效。这似乎适用于 PC 患者，因为长期 ADT 导致胸腺输出增加，循环近期胸腺移出细胞 (sjTREC) 的增加证明了这一点。此外，与 HSPC 对照组相比，CRPC 患者的肠道微生物群发生了变化，这与 sjTREC 显着相关。虽然健康志愿者的粪便可以恢复 ADT 功效，但 PC 患者的粪便却无法做到这一点。这些发现表明逆转 PC 患者肠道菌群失调和修复获得性免疫缺陷的潜在临床效用。
Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT. Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens. In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so. These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.
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DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G
影响因子：
2.8
作者：
Flammiger, Anna;Bayer, Florian;Trepel, Martin
通讯作者：
Trepel, Martin
影响因子：
16.6
作者：
Daisley BA;Chanyi RM;Abdur-Rashid K;Al KF;Gibbons S;Chmiel JA;Wilcox H;Reid G;Anderson A;Dewar M;Nair SM;Chin J;Burton JP
通讯作者：
Burton JP
影响因子：
16.6
作者：
Buque, Aitziber;Bloy, Norma;Galluzzi, Lorenzo
通讯作者：
Galluzzi, Lorenzo
影响因子：
0.7
作者：
Borodin, Yu. I.;Lomshakov, A. A.;Larionov, P. M.
通讯作者：
Larionov, P. M.