Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

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.

Current preclinical models to investigate human HR + breast cancer progression and response to immunotherapy in vivo are limited. Here, the authors demonstrate that mammary tumours driven by a synthetic progestin combined with an oral carcinogen recapitulate several immunobiological features of human HR + breast cancers.