Abstract LB066: Cytokine and chemokine screening reveals altered NK-DC-T cell crosstalk in the aged tumor microenvironment

Abstract The etiology and effects of age-related immune dysfunction in cancer remain incompletely understood. We previously demonstrated that the limited priming and function of CD8+ T cells in aged tumor-bearing mice are linked to altered NK-DC-T cell crosstalk within the aged tumor microenvironment (TME). Given that cytokines and chemokines play critical roles in NK-DC-T cell crosstalk, we further investigated which cytokines and chemokines might drive these defects in the aged TME. Tumor-bearing mice aged between 10 and 68 weeks were used to collect serum and tumor interstitial fluid samples, as well as tumor interstitial fluid samples from mice receiving CD40 agonist therapy. The collected samples were processed and analyzed using the Olink Target 48 mouse cytokine and chemokine panel. Consistent with the observed limited CD8+ T cell function, age-related changes in key cytokines and chemokines were identified in tumor interstitial fluid. We specifically observed a decline in effector cytokines, such as IL-2, IFN-γ, and TNF, that correlates with aging. Moreover, chemokines like CXCL9, essential for recruiting T cells, along with CCL4 and CCL2, important for myeloid recruitment, also showed a significant progressive decrease as age increased within the mouse TME. However, the age-related decline of these chemokines was not observed in the serum samples, suggesting no systematic decrease in peripheral circulation and further confirming that the age-related defects seen in the TME were likely tumor-driven. Notably, we found elevated levels of IL-2, IFN-γ, TNF, CXCL9, CCL4, and CCL2 in aged mice after treatment with a CD40 agonist. Additionally, these aged mice exhibited improved tumor control after treatment, indicating the crucial roles of these cytokines and chemokines in the aged TME. While CD40 agonist therapy has seen limited clinical success, our presented data demonstrate a novel approach that considers aging's effect on anti-tumor immunity. Additionally, our findings suggest a promising strategy for utilizing cytokines and chemokines in cancer treatment for older patients. Citation Format: Alex C. Chen, Marijana Rucevic, Sneha Jaiswal, Daniela Martinez, Cansu Yerinde, Keely Ji, Velita Miranda, Simon Forsberg, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Nir Hacohen, Debattama R. Sen. Cytokine and chemokine screening reveals altered NK-DC-T cell crosstalk in the aged tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB066.