PT  - JOURNAL ARTICLE
AU  - Safae Terrisse
AU  - Anne-Gaelle Goubet
AU  - Kousuke Ueda
AU  - Andrew Maltez Thomas
AU  - Valentin Quiniou
AU  - Cassandra Thelemaque
AU  - Garett Dunsmore
AU  - Emmanuel Clave
AU  - Melissa Gamat-Huber
AU  - Satoru Yonekura
AU  - Gladys Ferrere
AU  - Conrad Rauber
AU  - Hang Phuong Pham
AU  - Jean-Eudes Fahrner
AU  - Eugenie Pizzato
AU  - Pierre Ly
AU  - Marine Fidelle
AU  - Marine Mazzenga
AU  - Carolina Alves Costa Silva
AU  - Federica Armanini
AU  - Federica Pinto
AU  - Francesco Asnicar
AU  - Romain Daillère
AU  - Lisa Derosa
AU  - Corentin Richard
AU  - Pierre Blanchard
AU  - Bertrand Routy
AU  - Stéphane Culine
AU  - Paule Opolon
AU  - Aymeric Silvin
AU  - Florent Ginhoux
AU  - Antoine Toubert
AU  - Nicola Segata
AU  - Douglas G McNeel
AU  - Karim Fizazi
AU  - Guido Kroemer
AU  - Laurence Zitvogel
TI  - Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer
AID  - 10.1136/jitc-2021-004191
DP  - 2022 Mar 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e004191
VI  - 10
IP  - 3
4099  - http://jitc.bmj.com/content/10/3/e004191.short
4100  - http://jitc.bmj.com/content/10/3/e004191.full
SO  - J Immunother Cancer2022 Mar 01; 10
AB  - Background 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.Methods 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.Results 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.Conclusions These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.Data are available in a public, open access repository. The metagenomes have been deposited in NCBI under the bioproject PRJNA791751. Once public, they will be accessible using this link: https://www.ncbi.nlm.nih.gov/bioproject/791751.