Weight Loss Reverses the Effects of Aging and Obesity on Mammary Tumor Immunosuppression and Progression

Advanced age and obesity are major risk factors for breast cancer progression, including triple-negative breast cancer (TNBC). In this study, we interrogated (i) whether these factors interact to promote TNBC progression and (ii) whether weight loss mitigates the separate and combined effects of aging and obesity on TNBC. We demonstrate that aging and diet-induced obesity interact to promote TNBC growth in mice. Transcriptomic analysis revealed the suppression of antitumor immunity in tumors from aged and/or obese mice. Weight loss via intermittent calorie restriction reduced tumor growth and restored immune-related gene signatures to reverse the protumor effects of aging and/or obesity. Using publicly available genomic datasets from murine studies of obesity, weight loss, and TNBC, we identified a consensus transcriptomic signature of obesity-driven immunosuppression that predicted the survival of patients with breast cancer. This consensus signature was also suppressed by aging, obesity, and their combination. Intermittent calorie restriction reversed the effects of aging and/or obesity on the consensus signature. We conclude that aging and obesity interact to limit antitumor immunity and enhance TNBC progression and that these adverse effects can be disrupted by weight loss.

Advanced age and obesity are important risk factors for the development and progression of breast cancers, including TNBC. We demonstrate that the suppression of signatures of antitumor immunity is a common feature of accelerated tumor progression in TNBC. We show that weight loss achieved through calorie restriction can restore such markers. See related Spotlight, p. 437.