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

Abstract

Advanced age and obesity are each a major risk factor for breast cancer progression, including triple-negative breast cancer (TNBC). Here we interrogated: a) whether these factors interact to promote TNBC progression, and b) if weight loss mitigates the separate and combined effects of aging and obesity on TNBC. We demonstrate that aging and diet-induced obesity (DIO) interact to promote TNBC growth in mice. Transcriptomic analysis revealed suppression of antitumor immunity in tumors from aged and/or obese mice. Weight loss via intermittent calorie restriction (ICR) 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 survival of patients with breast cancer. This consensus signature was also suppressed by aging, obesity, and their combination. ICR reversed aging and/or obesity effects 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.