Abstract 2688: Age-associated changes in macrophage function and phenotype affects cancer development, and the efficacy of macrophage targeted anticancer therapies in murine melanoma model
Authors: Suresh Manasa , Li Xintang , Noonepalle Satish , Gajendran Nithya , Durr Marie , Quiceno-Torres David , Tan Karen , Villagra Alejandro 
Published: March 2024

Introduction: Aging of the immune system is a critical risk factor for chronic diseases, including cancer. Globally, cancer incidence is higher between 45 to 75 years of age and declines thereafter. However, the implications of aging in cancer are understudied, and aged populations are underrepresented, both in preclinical and clinical studies. The role of macrophages in cancer progression has gained attention as a tool and target for anticancer therapies. Tumor-associated macrophages (TAMs) mainly exhibit an anti-inflammatory M2 phenotype, promote an immunosuppressive tumor microenvironment (TME), and contribute to developing resistance against immunotherapies. Therefore, several strategies targeting the phenotype and function of TAMs are being explored, including inhibitors of histone deacetylases (HDACis), adoptive macrophage cell therapy, and CAR macrophages. Studies from our group have shown that ultra-specific HDAC6is can switch macrophages from anti-inflammatory, M2, to pro-inflammatory and antitumoral M1 phenotype with minimal cytotoxicity to cancer cells. However, it is unknown if age-related changes in macrophages affect such therapeutic strategies and the TME.

Objective: To characterize the changes in macrophage function and phenotype with aging and study its implications on the TME and the efficacy of macrophage-based anticancer therapies.

Methods: Wildtype mice of ages 6-8 WKS, 3-6 MO, 10-12 MO, and 20-24 MO were injected with SM1 melanoma cells to study tumor growth kinetics. Bone marrow-derived macrophages (BMDMs) isolated from tumor-bearing and healthy mice were polarized to M1 and M2 phenotype treated with HDAC6i to study age-associated changes in phagocytic activity, antigen presentation, and gene expression. Pathways associated with macrophage polarization were examined by flow cytometry, qRT-PCR, western blot, and single-cell proteomics. Immune cells in TME were characterized in flow cytometry and single-cell RNA and secretome analyses.

Results: Tumor growth in SM1 murine melanoma model was significantly slower in older mice when compared to younger mice. Aged macrophages demonstrated significant defect in polarization to M1 and M2 phenotypes that was more pronounced in BMDMs from tumor-bearing mice. Tumor-associated macrophages showed inefficient monocyte-to-macrophage transition, as also reflected in the single-cell secretome analysis. The ability of HDAC6i to enhance macrophage function was reduced among older mice.

Conclusions: The functional and phenotypic characteristics of macrophages change with age and can significantly affect tumor growth and the effectiveness of macrophage-targeted anticancer therapies. Our study highlights the importance of studying aging in macrophages and better representation of aged populations in preclinical and clinical studies.

Citation Format: Manasa Suresh, Xintang Li, Satish Noonepalle, Nithya Gajendran, Marie Durr, David Quiceno-Torres, Karen Tan, Alejandro Villagra. Age-associated changes in macrophage function and phenotype affects cancer development, and the efficacy of macrophage targeted anticancer therapies in murine melanoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2688.