Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer

Cell Rep. 2021 Jun 22;35(12):109285. doi: 10.1016/j.celrep.2021.109285.


Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO ABSTRACT.

Keywords: MDSC; TAM; adiposity; high-fat diet; immunosuppression; immunotherapy; mammary fat pad; metainflammation; microbiome; myeloid-derived suppressor cell; triple-negative breast cancer; tumor-associated macrophage.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / immunology*
  • Disease Progression
  • Female
  • Gastrointestinal Microbiome
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunosuppression Therapy
  • Immunotherapy
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Myeloid-Derived Suppressor Cells / metabolism
  • Obesity / complications*
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Estrogen / metabolism
  • Spleen / pathology
  • Tumor Burden
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology*


  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Receptors, Estrogen