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.

NK cells beat T cells at early breast cancer control

“…Finally, DMBA/ MPA-driven mammary carcinomas resemble human HR + BC in their limited sensitivity to ICBs targeting programmed cell death 1 (PDCD1, best known as PD-1). 4 Intriguingly, we found that DMBA/MPA-driven oncogenesis is not altered by the Rag2 −/genotype (which imposes a defect in T cells and B cells, but largely spares NK cells), nor by the antibody-mediated co-depletion of CD4 + and CD8 + T cells. Conversely, the depletion of cells expressing killer cell lectin like receptor K1 (KLRK1, best known as NKG2D), which encompass NK cells and a fraction of T cells, phenocopied the detrimental effects of the Rag2 −/-Il2rg −/genotype on disease emergence and progression.…”

“…We found that these tumors are histologically and transcriptionally similar to human luminal B (highly proliferative HR + HER2 − ) BC, and emerge by an oncogenic process that depends on the transcriptional activity of estrogen receptor 1 (ESR1) and is coupled to the evasion of immunosurveillance. 4 Consistent with this notion, oncogenesis and tumor progression (culminating in the death of tumor-bearing mice) are accelerated in highly immunodeficient Rag2 −/-Il2rg −/mice (which lack T cells, B cells and NK cells), as well as in mice lacking the key immune effector interferon gamma (IFNG). 4 Moreover, palpable DMBA/MPA-driven mammary carcinomas (1) exhibit a transcriptional signature enriched in genes involved in cell cycle progression and proliferation, but deprived of genes involved in immunological functions, and (2) are scarcely infiltrated by immune effector cells as they display a CD4 compartment that is polarized toward immunosuppression by CD4 + CD25 + FOXP3 + regulatory T (T REG ) cells.…”

“…4 Consistent with this notion, oncogenesis and tumor progression (culminating in the death of tumor-bearing mice) are accelerated in highly immunodeficient Rag2 −/-Il2rg −/mice (which lack T cells, B cells and NK cells), as well as in mice lacking the key immune effector interferon gamma (IFNG). 4 Moreover, palpable DMBA/MPA-driven mammary carcinomas (1) exhibit a transcriptional signature enriched in genes involved in cell cycle progression and proliferation, but deprived of genes involved in immunological functions, and (2) are scarcely infiltrated by immune effector cells as they display a CD4 compartment that is polarized toward immunosuppression by CD4 + CD25 + FOXP3 + regulatory T (T REG ) cells. Finally, DMBA/ MPA-driven mammary carcinomas resemble human HR + BC in their limited sensitivity to ICBs targeting programmed cell death 1 (PDCD1, best known as PD-1).…”

“…3 Apparently at odds with this notion, our recent findings indicate that CD8 + CTLs fail to control 7,12-dimethylbenz[a]anthracene (DMBA)-initiated, medroxyprogesterone (MPA)-accelerated mammary carcinomas emerging in immunocompetent C57BL/6 mice, whereas natural killer (NK) cells are the main effectors of early cancer immunosurveillance in this setting. 4 An estimated 276,480 new cases of breast cancer (BC) and 42,170 new BC-related deaths have been quantified to affect women living in the US in 2020, a majority of which originate from hormone receptor (HR)-positive (luminal A and luminal B) disease. 5 Thus, despite the progress achieved over the past decades on the early detection and clinical management of HR + BC, many women still succumb to this devastating disease, calling for the development of therapeutic regimens with superior clinical activity.…”

“…Conversely, the depletion of cells expressing killer cell lectin like receptor K1 (KLRK1, best known as NKG2D), which encompass NK cells and a fraction of T cells, phenocopied the detrimental effects of the Rag2 −/-Il2rg −/genotype on disease emergence and progression. 4 Moreover, while MCA-driven sarcomas emerging in immunocompetent, syngeneic mice can be transplanted (at least in a fraction of cases) into immunocompetent recipients, reflecting the ability of T cells from the original host to limit the antigenicity of evolving tumors, 3 the same did not hold true for DMBA/MPAdriven carcinomas. 4 That said, the therapeutic efficacy of anthracycline-based chemotherapy and/or the experimental caloric restriction mimetics (CRMs) hydroxycitrate and nicotinamide (both of which potently induce autophagy) against established DMBA/MPA-driven carcinomas can be abrogated by the antibody-mediated co-depletion of CD4 + and/or CD8 + T cells.…”