Absence of nuclear receptors LXRs impairs immune response to androgen deprivation and leads to prostate neoplasia

PLoS Biol. 2020 Dec 7;18(12):e3000948. doi: 10.1371/journal.pbio.3000948. eCollection 2020 Dec.

Abstract

Chronic inflammation is now a well-known precursor for cancer development. Infectious prostatitis are the most common causes of prostate inflammation, but emerging evidence points the role of metabolic disorders as a potential source of cancer-related inflammation. Although the widely used treatment for prostate cancer based on androgen deprivation therapy (ADT) effectively decreases tumor size, it also causes profound alterations in immune tumor microenvironment within the prostate. Here, we demonstrate that prostates of a mouse model invalidated for nuclear receptors liver X receptors (LXRs), crucial lipid metabolism and inflammation integrators, respond in an unexpected way to androgen deprivation. Indeed, we observed profound alterations in immune cells composition, which was associated with chronic inflammation of the prostate. This was explained by the recruitment of phagocytosis-deficient macrophages leading to aberrant hyporesponse to castration. This phenotypic alteration was sufficient to allow prostatic neoplasia. Altogether, these data suggest that ADT and inflammation resulting from metabolic alterations interact to promote aberrant proliferation of epithelial prostate cells and development of neoplasia. This raises the question of the benefit of ADT for patients with metabolic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / immunology
  • Androgens / metabolism
  • Animals
  • Disease Models, Animal
  • Immunity / immunology
  • Immunity / physiology*
  • Liver X Receptors / genetics
  • Liver X Receptors / immunology
  • Liver X Receptors / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Neoplasms / etiology
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Prostate / metabolism*
  • Prostate / pathology
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Tumor Microenvironment

Substances

  • Androgen Antagonists
  • Androgens
  • Liver X Receptors
  • Receptors, Cytoplasmic and Nuclear

Grant support

This work was supported by institutional support from Centre National de la Recherche Scientifique (https://www.cnrs.fr/), Institut National de la Santé et de la Recherche Médicale (https://www.inserm.fr/), Université Clermont Auvergne (https://www.uca.fr/), and by grants from ERFD (https://www.europe-en-france.gouv.fr/fr/) and AURA region (https://www.auvergnerhonealpes.fr/) (CPER/FEDER DEFI EPICURE AV001826/AV0010859), ARTP (Association de Recherche sur les Tumeurs Prostatiques, http://www.iartp.org/), EDC-CaP Plan Cancer 2014-2019 (https://www.e-cancer.fr/Plan-cancer/) INCa (Institut National du cancer, https://www.e-cancer.fr/) and CAP/TransCAP project INCa, CLARA (Canceropole Lyon Auvergne Rhône Alpes, https://www.canceropole-clara.com/), AURA region. LB was funded by ERFD and AURA region (CPER/FEDER DEFI EPICURE AV0010836). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.