Immune system and intestinal microbiota determine efficacy of androgen depletion therapy against prostate cancer.

Author:

Terrisse Safae1,Goubet Anne-Gaëlle2,Ueda Kosuke3,Thomas Andrew M.4,Quiniou Valentin5,Thelemaque Cassandra2,Dunsmore Garett2,Clave Emmanuel6,Gamat-Huber Melissa7,Yonekura Satoru2,Derosa Lisa8,Culine Stephane9,Opolon Paule10,Ginhoux Florent2,Toubert Antoine6,Segata Nicola4,McNeel Douglas G.11,Fizazi Karim12,Kroemer Guido13,Zitvogel Laurence14

Affiliation:

1. INSERM U1015, Gustave Roussy Cancer Campus, Medicale Oncology, Hôpital Saint Louis, Paris, France;

2. INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, France;

3. Department of Urology, Kurume University School of Medicine, Kurume, Japan;

4. Department CIBIO, University of Trento, Trento, Italy;

5. Parean Biotechnologies, Saint-Malo, France;

6. Université de Paris, INSERM UMRS-1160, Institut de Recherche Saint-Louis, Paris, France;

7. University of Wisconsin Carbone Cancer Center Madison, Wisconsin, USA, Madison, WI;

8. Department of Cancer Medicine, Gustave Roussy Cancer Campus, Paris-Sud University, department of Cancer Medicine, Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France;

9. Department of Medical Oncology, Hospital Saint-Louis, Paris, France;

10. Institut Gustave Roussy, Villejuif, France;

11. University of Wisconsin Carbone Cancer Center, Madison, WI;

12. Gustave Roussy and University of Paris-Saclay, Villejuif, France;

13. U1138 Inserm, Metabolism, Cancer and Immunity, Gustave Roussy Cancer Center, Villejuif, France;

14. U1015 INSERM, Gustave Roussy Cancer Campus, Paris Saclay University, Villejuif, France;

Abstract

168 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). While it is recognized that ADT has an immunomodulatory effect, little is known about the intestinal microbiome effect on therapeutic outcome of ADT. Methods: 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 to analyze their feces and blood specimen. 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 appear 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 to HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy. Conclusions: These findings suggest that reversing the intestinal dysbiosis and repairing acquired immune defects in PC patients have a potential impact on the therapeutic outcome of ADT.

Funder

None.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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