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Tumor-associated macrophage functional heterogeneity is driven by niche diversity in breast cancer

ABSTRACT: The concept of macrophage niches has redefined the classification of macrophages, moving beyond ontogeny and function to encompass the mutually beneficial loop of signals in a given tissue environment. As such, tissue-resident macrophages adapt to local environmental signals within and between tissues to acquire specific functional adaptations. Neoplastic transition transforms the tissue environment, which then raises the question as to how existing macrophage subsets and their niche contribute to the tumor-associated macrophage (TAM) compartment. By combining single cell RNA sequencing and 2-photon imaging, we discovered that considerable TAM heterogeneity in mammary breast tumor is driven by niches that exist prior to tumor development, macrophage localization within the tumor and the stage of tumor malignancy. The differentiation of TAM subsets was associated with distinct signaling paths, homing and transcription factor signatures. We find similar functional heterogeneity in human breast TAMs. In overview, we show that specific niches within the tumor rather than defined activation states (e.g. the M1/M2 dichotomy) are the major drivers of TAM plasticity and heterogeneity. The distinctions created by this analysis show how treatments of different tumor indications should propose targeting specific TAMs at this niche/pathway level.

ORGANISM(S): Mus musculus

PROVIDER: GSE184096 | GEO | 2022/05/05

REPOSITORIES: GEO

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Macrophages are metabolically heterogenous within the tumor microenvironment

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Project description:Recent studies have shown the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and immunotherapy response. A question that remains is whether the ECM is directly educating the immune phenotypes seen in cancer. We identified a tumor-associated macrophage (TAM) population correlated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether ECM was capable of generating the TAM phenotype seen, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissues. ECM educated macrophages have a tissue remodeling and immunoregulatory phenotype, inducing altered T cell function. We conclude that the tumor ECM is directly educating this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

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2010-05-16 | E-GEOD-18295 | biostudies-arrayexpress

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2020-09-09 | GSE157673 | GEO

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