Abstract 1737: Efficacy of immunotherapy is attenuated with age in triple-negative breast cancer

Age is associated with increasing immune dysfunction that includes significant changes to both the innate and adaptive immune responses. These age-related changes could present limitations to the application of immunotherapy in breast cancer, as over 50% of patients are over 60 years old at diagnosis. Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, but remains the only subtype that lacks any type of targeted therapy. Early results from clinical trials of anti-PD-1 therapy in metastatic TNBC patients have shown promise, with approximately 20% of patients demonstrating a partial or complete response. While TNBC incidence is similar in young and old patients, differences in disease progression and outcome with age suggest that treatment needs to be tailored to both age as well as breast cancer subtype. It is not known whether age impacts response to immunotherapy, particularly checkpoint blockade, in breast cancer. Using multiple preclinical models of age-dependent TNBC, we found that aged mice had significantly reduced ability to respond to either anti-PD-L1 or anti-CTLA4. Old mice showed decreased numbers of circulating CD4-positive and CD8-positive T cells, as well as NK cells. Furthermore, PD-1 expression was increased on these populations relative to young mice, suggesting increased immune cell exhaustion with age. The old mice also demonstrated increased central and effector memory T cells, but decreased naive T cells compared to young mice, consistent with reports from clinical studies of aged individuals. These findings suggest decreased ability to respond to neoantigens with age. Importantly, using high-content flow cytometric analyses and RNA-seq, we defined cellular and molecular mechanisms that correlate with response in young mice that are attenuated or lacking in old mice. Many of the differentially expressed genes that defined response to anti-CTLA4 in young mice and resistance to treatment in the old mice were also predictors of response to immunotherapy in cancer patients. Our data suggested novel combination therapies that, when combined with checkpoint blockade, improved responses and survival in old mice with TNBC. Our findings should suggest age-stratified treatments to ensure that TNBC patients see the most benefit possible and prevent overtreatment with futile and harsh chemotherapies. Citation Format: Sandra S. McAllister, Jaclyn Sceneay, Tyler Laszewski, Molly DeCristo, Jessalyn Ubellacker, Kristin Wilson, Yuanbo Qin, John Hutchinson. Efficacy of immunotherapy is attenuated with age in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1737.