Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer

• Published in: Nature communications Vol. 11; no. 1; pp. 3819 - 18
• Main Authors: Buqué, Aitziber, Bloy, Norma, Perez-Lanzón, Maria, Iribarren, Kristina, Humeau, Juliette, Pol, Jonathan G., Levesque, Sarah, Mondragon, Laura, Yamazaki, Takahiro, Sato, Ai, Aranda, Fernando, Durand, Sylvère, Boissonnas, Alexandre, Fucikova, Jitka, Senovilla, Laura, Enot, David, Hensler, Michal, Kremer, Margerie, Stoll, Gautier, Hu, Yang, Massa, Chiara, Formenti, Silvia C., Seliger, Barbara, Elemento, Olivier, Spisek, Radek, André, Fabrice, Zitvogel, Laurence, Delaloge, Suzette, Kroemer, Guido, Galluzzi, Lorenzo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 14/19; 38/91; 49; 59; 631/67/1059; 631/67/1347; 631/67/2195; 631/67/580; 64/110; 64/60; 9,10-Dimethyl-1,2-benzanthracene; Acetic acid; Animals; Anthracene; Breast cancer; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - therapy; Carcinogenesis - drug effects; Carcinogenesis - immunology; Carcinogens; Dietary supplements; Disease Progression; Effector cells; ErbB-2 protein; Female; Humanities and Social Sciences; Humans; Immune checkpoint; Immunology; Immunosurveillance; Immunotherapy; Immunotherapy - methods; In vivo methods and tests; Interferon; Interferon Type I - immunology; Interferon Type I - metabolism; Life Sciences; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - prevention & control; Medroxyprogesterone Acetate; Metastases; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Niacinamide - administration & dosage; Nicotinamide; Progestin; Receptor, ErbB-2 - immunology; Receptor, ErbB-2 - metabolism; Receptors; Science; Science (multidisciplinary); Survival Analysis; Tumorigenesis; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17644-0

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.