Abstract 6139: Changes in macrophage phenotype and function with aging affects tumor growth and tumor microenvironment in murine cancer models

Abstract Introduction: Tumor-associated macrophages (TAMs) constitute a significant population of immune cells in the tumor microenvironment (TME), mainly exhibiting an anti-inflammatory M2-like phenotype. They secrete angiogenic growth factors that support tumor growth with an immunosuppressive TME and contribute to developing resistance against immunotherapies. Therefore, there is an increasing effort to switch TAMs from protumoral M2-like to antitumoral and pro-inflammatory M1-like phenotype. Aging is a critical risk factor, with global cancer incidences increasing from 45 to 75 years of age and declining thereafter. The reason behind this decline beyond 75 years of age is unknown but needs further investigation. With the underrepresentation of aged population in preclinical and clinical studies, the role of aging in cancer development and the TME are understudied. Considering the multidimensional role of macrophages in the TME, this study determines the effects of age-associated changes in macrophage function and phenotype on tumor development. Objective: To study the changes in macrophage biology with aging and understand the implications of aging macrophages on the TME in murine cancer models. Methods: Wildtype mice of ages 6-8 WKS, 3-6 MO, 10-12 MO, and 20-24 MO were implanted with tumor cells (SM1 melanoma, 4T1 breast cancer) to study tumor growth kinetics. Immune cell profiling of TME, including TAMs, was performed using flow cytometry, single-cell RNAseq, and secretome analysis. Bone marrow-derived macrophages isolated from tumor-bearing and healthy mice of the above four age groups were polarized to M1 and M2 phenotypes to study age- and cancer-associated changes in macrophage function, phenotype, and metabolic signature. The changes in macrophage cytokine and chemokine secretion levels with aging were determined by multiplex ELISA assays. Results: Tumor growth in older mice was significantly slower than in younger mice. A distinct change in immune cell populations within the TME and reduced secretion profile of TAMs with aging was observed from single-cell analyses. Additionally, the single-cell secretome analysis reflected an inefficient monocyte-to-macrophage transition in tumors of older mice. The defect in macrophage polarization to M1- and M2-like phenotypes with aging complemented with the sub-optimal function (phagocytosis, antigen presentation, and migration) and metabolic signatures of aged macrophages. Conclusions: The phenotypic, functional, and metabolic changes in macrophages with aging significantly affect tumor growth in murine cancer models. Our study further emphasizes the important role of macrophages in the TME and the need for better representation of aged populations in preclinical and clinical studies. Citation Format: Manasa Suresh, Marie Durr, Xintang Li, Bryan Weselman, Francisco Tapia Belmonte, Nithya Gajendran, David Quiceno-Torres, Sonia Sebaoui, Adhithi Rajesh, Matias Hepp, Alexis Salas-Burgos, Satish Noonepalle, Alejandro Villagra. Changes in macrophage phenotype and function with aging affects tumor growth and tumor microenvironment in murine cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6139.