Abstract PS17-04: Immune checkpoint blockade reprograms tumor microenvironment and systemic immune landscape in obesity associated triple negative breast cancer
Authors: Pingili Ajeeth K , Chaib Mehdi , Sipe Laura M , Miller Emily J , Teng Bin , Sharma Rahul , Abdallah Qusai AI , Daria Deidra , Sekhri Radhika , Jo Heejoon , Tahliyah Mims S , Hayes D. Neil , Pierre Joseph F , Makowski Liza 
Published: February 2021

Abstract
Few targeted therapies exist for triple negative breast cancer (TNBC), an aggressive and deadly subtype. Obesity exacerbates poor outcomes in TNBC due to elevated invasion and metastasis leading to increased mortality. Obesity has paradoxically been shown to improve immune checkpoint therapies in other cancers, yet the underlying mechanisms are unclear. Despite being an inflammatory state, obesity increases immune checkpoint ligands PD-1 and PD-L1 which drives immunosuppression. Thus, we tested the hypothesis that obesity-driven changes to the immune milieu will improve ICB efficacy in TNBC. Syngeneic tumors were generated via orthotopic engraftment of E0771 basal-like TNBC cell line into age-matched immune-competent C57BL/6J female littermates on obesogenic or low fat diets. Mice were treated with anti-mouse anti-PD-1 or isotype control (IgG2a) every 3rd day until sacrifice. Obese mice gained almost 2-fold great body weight and 3.6-fold greater adiposity compared to lean mice and immunotherapy did not impact weights or body composition. Obesity led to immunosuppression systemically in bone marrow and spleen in tumor-free mice, which was exacerbated in tumor-bearing mice. Obese mice had significantly greater tumor progression and fewer regressed tumors at endpoint vs. lean mice. Anti-PD-1 significantly reduced tumor progression in obese mice with 4.2-fold reduction in volume and 5.7-fold reduction in tumor weights in obese mice vs. isotype controls. Anti PD-1 significantly reduced immunosuppressive cells including M2-like tumor associated macrophages and monocytic and granulocytic myeloid derived suppressor cells (MDSC) and raised anti-tumor M1-like macrophages, cytotoxic CD8+ T cells, and dendritic cells. Last, the microbiome has potent effects on responses to anti-tumor therapies such as chemotherapy and immune checkpoint blockade. Obesity is a major regulator of the gut microbiome. We found that beneficial bacteria belonging to genus Bifidobacterium was higher in lean compared to obese mice, which could limit tumor progression and lead to greater regression through robust anti-tumor immunity. In obese mice, beneficial bacteria belonging to genus Ruminococcus, Adlercreutzia, Corpococcus that promote anti-tumor immunity increased with anti PD-1 immunotherapy. In sum, we show for the first time that obesity-induced systemic and microenvironmental immunosuppression augmented tumor incidence and tumor progression. Furthermore, anti-PD-1 immune checkpoint blockade successfully reduced tumor progression in obese mice through reprogramming not only the TME but systemic immune milieu as well. Immunosuppressive targets unique to the obese TME could be targeted in concert with checkpoint inhibitors in future interventions to enhance durable anti-tumor immunity.
Citation Format: Ajeeth K Pingili, Mehdi Chaib, Laura M Sipe, Emily J Miller, Bin Teng, Rahul Sharma, Qusai AI Abdallah, Deidra Daria, Radhika Sekhri, Heejoon Jo, Mims S Tahliyah, D. Neil Hayes, Joseph F Pierre, Liza Makowski. Immune checkpoint blockade reprograms tumor microenvironment and systemic immune landscape in obesity associated triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-04.