Abstract IA023: TIME and Age: Impact of age on the tumor immune microenvironment and response to therapy
Authors: McAllister Sandra S. 
Published: March 2021

Abstract
Breast cancer affects women of all ages yet young (&lt;40) and older women (&gt;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 &lt;40 and &gt;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 &lt;40 and &gt;65, IFNg, IFNa, and inflammatory responses were enriched only in patients &lt;40. Hence, immune priming and T-cell inflamed phenotypes appear to be functional prior to treatment in young mice and are likewise enriched in women &lt;40, but not &gt;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.