Abstract C016: Age dictates immune response within the tumor microenvironment of triple negative breast cancer
Authors: Spasic Milos , Parsons Adrienne , Recko Abigail , Mittendorf Elizabeth , van Galen Peter , McAllister Sandra 
Published: November 2024

Age is the biggest risk factor for developing most forms of cancer. In breast cancer, over 50% of patients are over 60 years old; however, less than 25% of patients enrolled in clinical trials are in this age bracket. Furthermore, most mouse modeling is performed in young mice, meaning that from preclinical through clinical stages patients ages are not accurately reflected in trials designs. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with no targeted therapies, so many treatment strategies utilize chemotherapy in combination with immunotherapy – which relies on a functional immune response. It is well known that immune function declines as we age, and thus therapeutic responses may differ with age. It is yet unclear how the tumor immune microenvironment changes with age, and how this may impact therapeutic response. Here, we utilize a mouse model which mimics hallmarks of human immune aging to understand how age impacts TNBC immune responses to dictate disease progression and therapeutic response. Immunologically young (8 weeks old) and aged (∼12 months old) FVB mice were orthotopically injected with syngeneic Met1 TNBC cells. Once tumors became palpable, mice were treated with paclitaxel chemotherapy or vehicle control and/or anti-PDL1 immunotherapy to mimic first-line therapeutic strategies. Tumors grew significantly faster in young control mice compared to aged, but young mice had a more robust response to therapy. Notable, only young mice had a significant benefit of combo therapy over monotherapy alone. Despite aged mice having more circulating CD8+ and CD4+ T cells, tumors in aged mice had significantly more infiltration of CD8+ cytotoxic T cells and FOXP3+ inhibitory T-regulatory cells compared to young control mice, yet only tumors in young mice exhibited an increase in T cell infiltration with therapy. Additionally, the ratio of CD8+ T cells and FOXP3+ Tregs was unchanged with age or treatment. Depletion of either CD8+ or CD4+ T cells led to a complete loss of age-associated differences in tumor growth. RNA sequencing analysis suggests that infiltrating T cells in aged mice may be exhausted due to a chronic interferon (IFN) phenotype, indicated by enrichment of IFN-alpha, IFN-gamma, and IL2 pathways, as well as increased expression of immune exhaustion markers PD1, CTLA4, TIM3 and LAG3. Neutralization of IFN-gamma blocks therapeutic response to anti-PDL1 in young mice but has no impact on aged mice. Analysis of published single cell RNAseq data indicated the same IFN response pathways enriched with age in human TNBC. These results demonstrate that the aging tumor immune microenvironment significantly impacts tumor progression and therapeutic response and suggest that targeting IFN signaling may lead to improved therapeutic responses. Together these findings establish a significant impact of immune aging on TNBC disease progression and response to therapy, highlighting the importance of developing age- stratified treatment strategies to improve responses in patients of all ages.

Citation Format: Milos Spasic, Adrienne Parsons, Abigail Recko, Elizabeth Mittendorf, Peter van Galen, Sandra McAllister. Age dictates immune response within the tumor microenvironment of triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C016.