1. Tumor-associated macrophages impair NK cell IFN-γ production and contribute to tumor progression in clear cell renal cell carcinoma.
- Author
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Núñez SY, Trotta A, Regge MV, Amarilla MS, Secchiari F, Sierra JM, Santilli MC, Gantov M, Rovegno A, Richards N, Ameri C, Ríos Pita H, Rico L, Mieggi M, Vitagliano G, Blas L, Friedrich AD, Domaica CI, Fuertes MB, and Zwirner NW
- Subjects
- Humans, Animals, Mice, Disease Progression, Cell Line, Tumor, Tumor Microenvironment immunology, NK Cell Lectin-Like Receptor Subfamily K metabolism, Hepatitis A Virus Cellular Receptor 2 metabolism, Hepatitis A Virus Cellular Receptor 2 immunology, Programmed Cell Death 1 Receptor metabolism, Killer Cells, Natural immunology, Carcinoma, Renal Cell immunology, Carcinoma, Renal Cell pathology, Interferon-gamma metabolism, Interferon-gamma immunology, Kidney Neoplasms immunology, Kidney Neoplasms pathology, Tumor-Associated Macrophages immunology, Tumor-Associated Macrophages metabolism
- Abstract
Tumor-associated macrophages (TAM) are abundant in several tumor types and usually correlate with poor prognosis. Previously, we demonstrated that anti-inflammatory macrophages (M2) inhibit NK cell effector functions. Here, we explored the impact of TAM on NK cells in the context of clear-cell renal cell carcinoma (ccRCC). Bioinformatics analysis revealed that an exhausted NK cell signature strongly correlated with an M2 signature. Analysis of TAM from human ccRCC samples confirmed that they exhibited an M2-skewed phenotype and inhibited IFN-γ production by NK cells. Moreover, human M0 macrophages cultured with conditioned media from ccRCC cell lines generated macrophages with an M2-skewed phenotype (TAM-like), which alike TAM, displayed suppressive activity on NK cells. Moreover, TAM depletion in the mouse Renca ccRCC model resulted in delayed tumor growth and reduced volume, accompanied by an increased frequency of IFN-γ-producing tumor-infiltrating NK cells that displayed heightened expression of T-bet and NKG2D and reduced expression of the exhaustion-associated co-inhibitory molecules PD-1 and TIM-3. Therefore, in ccRCC, the tumor microenvironment polarizes TAM toward an immunosuppressive profile that promotes tumor-infiltrating NK cell dysfunction, contributing to tumor progression. In addition, immunotherapy strategies targeting TAM may result in NK cell reinvigoration, thereby counteracting tumor progression., (© 2024 Wiley‐VCH GmbH.)
- Published
- 2024
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