Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

Nat Commun. 2020 Jul 30;11(1):3819. doi: 10.1038/s41467-020-17644-0.

Abstract

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / therapy*
  • Carcinogenesis / drug effects
  • Carcinogenesis / immunology
  • Disease Progression
  • Female
  • Humans
  • Immunotherapy / methods*
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / immunology
  • Mammary Neoplasms, Experimental / prevention & control
  • Medroxyprogesterone Acetate
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Niacinamide / administration & dosage*
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / metabolism
  • Survival Analysis

Substances

  • Interferon Type I
  • Niacinamide
  • 9,10-Dimethyl-1,2-benzanthracene
  • Medroxyprogesterone Acetate
  • Receptor, ErbB-2