Abstract IA023: TIME and Age: Impact of age on the tumor immune microenvironment and response to therapy

Breast cancer affects women of all ages yet young ( 65) experience worse survival than their middle-aged counterparts. Age is associated with increasing immune dysfunction, yet the clinical implications of age-related changes are unknown, as women 65 years of age are under-represented in clinical trials. We hypothesized that both young and older immunological age impact breast cancer outcomes and present unique obstacles to therapeutic efficacy. Using pre-clinical triple-negative breast cancer (TNBC) models, we had found that bone marrow progenitor cells upregulate granulin (GRN), a secreted pro-inflammatory factor. Once mobilized from the marrow, those cells infiltrate tumors where GRN generates a tumor-supportive microenvironment. High GRN also correlated with reduced survival in our cohort of breast cancer patients. When we performed the same experiments in immunologically old mice (12-18 mos), tumors grew slower and GRN+ cell recruitment was reduced. GRN+ bone marrow cells from young donor mice rescued tumor growth in aged recipients, indicating that pro-tumor immunity resides in the marrow and explaining the aggressive TNBC growth in young cohorts. We next asked if age impacts immune checkpoint blockade (ICB) efficacy, using a 4T1 TNBC model to evaluate anti-PD-L1 or anti-CTLA4 monotherapy. Young mice responded to anti-PD-L1 and anti-CTLA4 with significantly prolonged survival; however, aged mice derived no benefit from ICB therapy. In response to ICB, tumors in young mice had significantly higher CD8+:Treg ratios and were enriched for inflammatory and interferon (IFN)-gamma response genes, thus revealing active anti-tumor immunity in young but not aged mice. Importantly, IFN-alpha, IFN-gamma, and inflammatory pathways were enriched in young relative to aged isotype control mice. When we analyzed METABRIC gene expression data for TNBC patients 65, IFNg, IFNa, and inflammatory responses were enriched only in patients 65. To stimulate immune priming in aged mice, we evaluated the STING agonist, DMXAA, which significantly prolonged survival in combination with ICB in the aged cohort. We are currently performing a pre-clinical study mirroring the IMpassion031 trial, which recently reported improved pathological complete response rates to neoadjuvant atezolizumab (anti-PD-L1)+nab-paclitaxel in TNBC. In a Met1 TNBC model, tumors grew slower with improved survival in the untreated aged mice. Young and aged mice responded to paclitaxel alone and anti-PD-L1 monotherapy; however, anti-PD-L1 provided additional benefit to paclitaxel only in young mice, similar to the trend reported in the IMpassion031 trial. Our results support a model whereby the net effects of pro- and anti-tumor immunity change with age and affect breast cancer outcomes. Understanding age-related immune function should enable us to design age-stratified breast cancer therapies. Citation Format: Sandra S. McAllister. TIME and Age: Impact of age on the tumor immune microenvironment and response to therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA023.