Age-related changes in myeloid cells and their impact on subcutaneous melanoma growth in mice
Advancing age increases cancer risk due to DNA damage accumulation and a decline in immune function. While aging is known to reduce adaptive immunity, it also leads to an increase in immunosuppressive myeloid cells, which promote tumor progression and are linked to poorer outcomes in melanoma. This study aims to characterize how aging alters Gr-1+ myeloid cells function and their impact on melanoma growth and immunotherapy response. Subcutaneous tumor growth using several YUMM melanoma cell lines were evaluated in 2-, 6-, and 12-month old wild type mice. Immune profiling of tumor-bearing and age-matched healthy mice was performed via flow cytometry and single-cell RNA sequencing. Gr-1+ myeloid cells were isolated to evaluate CD8+ T cell suppression, reactive oxygen species production and extracellular trap formation. Altered tumor growth, Gr-1+ myeloid cells function and immune checkpoint therapy response were evaluated comparing 2-month and 6-month old wild type and syngeneic myeloperoxidase-deficient mice. Aging only accelerated YUMM1.7 tumor growth and was associated with increased myeloid-derived suppressor cells, regulatory T cells, and exhausted T cells. Gr-1+ myeloid cells from aged, tumor-bearing mice showed enhanced CD8+ T cell suppression, reactive oxygen species production, and extracellular trap formation. Myeloperoxidase deficiency abrogated age-dependent tumor growth and improved immunotherapy response in YUMM1.7 tumor-bearing mice. Our findings highlight a context-dependent immune response to melanoma with aging, indicating that age-related variations in melanoma growth and immunotherapy response are not ubiquitous. Age-accelerated tumor growth is associated with increased immunosuppressive cell populations alongside enhanced Gr-1+ myeloid cell-mediated immunosuppression driven in part by myeloperoxidase. Myeloperoxidase deficiency effectively reduced Gr-1+ myeloid cell immunosuppression, decreased reactive oxygen species, and diminished extracellular trap formation, thereby eliminating age-dependent differences in tumor growth and immunotherapy response. This work underscores the impact of aging on Gr-1+ myeloid cells on cancer progression and immunotherapy efficacy.