Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer
Ajeeth K. Pingili, Mehdi Chaib, Laura M. Sipe, Emily J. Miller, Bin Teng, Rahul Sharma, Johnathan R. Yarbro, Sarah Asemota, Qusai Al Abdallah, Tahliyah S. Mims, Tony N. Marion, Deidre Daria, Radhika Sekhri, Alina M. Hamilton, Melissa A. Troester, Heejoon Jo, Hyo Young Choi, D. Neil Hayes, Katherine L. Cook, Ramesh Narayanan, Joseph F. Pierre, Liza Makowski
Abstract
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.