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Published on: November 28, 2019
Tumor microenvironment profoundly modifies functional status of macrophages: peritoneal and tumor-associated
Dayron Rodríguez1, Risset Silvera, Roberto Carrio
1Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Macrophages are key players in the inflammatory response. In this study, we tested the hypothesis that although all macrophage subpopulations in tumor hosts are affected by the disease, it is the close proximity to the tumor that induces major alterations in these cells. We compared tumor-associated macrophages (TAMs) with peritoneal macrophages from mice bearing D1-DMBA-3 mammary tumors (T-PEMs). Our results show that TAMs downregulate IL-12p70 but upregulate IL-12p40, IL-23, IL-6 and IL-10. Some NFκB and C/EBP transcription factors family members are decreased in TAMs; however NFκBp50 homodimers, STAT1/pSTAT1 and STAT3/pSTAT3 are overexpressed. Furthermore, while TAMs block T-cell proliferation and are more prone to apoptosis compared to T-PEMs, both types of macrophages have an impaired phagocytic capacity. Moreover, TAMs constitutively express iNOS and produce nitric oxide but do not express arginase and are Gr-1(high) and CD11b(low). Collectively, our analysis of two spatially distinct macrophage subpopulations in tumor-bearing mice revealed that the tumor modulates them differently into two molecularly and functionally dissimilar macrophage subpopulations.
Insights
Tumor-associated macrophages (TAMs) exhibit distinct molecular and functional changes compared to peritoneal macrophages. Proximity to the tumor significantly alters macrophage behavior, impacting immune responses and cell function.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Biology
Background:
- Macrophages are crucial in regulating inflammatory responses.
- Tumor microenvironments significantly influence immune cell behavior.
- Understanding macrophage heterogeneity is vital for cancer research.
Purpose of the Study:
- To investigate how tumor proximity affects macrophage subpopulations.
- To compare tumor-associated macrophages (TAMs) with peritoneal macrophages (T-PEMs) in tumor-bearing mice.
- To elucidate the molecular and functional differences induced by the tumor microenvironment.
Main Methods:
- Comparison of TAMs and T-PEMs from D1-DMBA-3 mammary tumor-bearing mice.
- Analysis of cytokine expression profiles (IL-12p70, IL-12p40, IL-23, IL-6, IL-10).
- Assessment of transcription factor expression (NFκB, C/EBP, STAT1, STAT3) and macrophage markers (Gr-1, CD11b).
- Evaluation of T-cell proliferation, apoptosis, and phagocytic capacity.
Main Results:
- TAMs showed altered cytokine profiles, including downregulated IL-12p70 and upregulated IL-12p40, IL-23, IL-6, and IL-10.
- Specific transcription factors (NFκBp50 homodimers, STAT1/pSTAT1, STAT3/pSTAT3) were overexpressed in TAMs.
- TAMs exhibited suppressed T-cell proliferation, increased apoptosis, and impaired phagocytosis compared to T-PEMs.
- TAMs constitutively expressed iNOS and produced nitric oxide, lacking arginase expression, and displayed Gr-1(high)/CD11b(low) phenotype.
Conclusions:
- Tumor proximity induces significant molecular and functional divergence between TAMs and T-PEMs.
- TAMs possess distinct characteristics that may contribute to immune evasion and tumor progression.
- These findings highlight the complex modulation of macrophages by the tumor microenvironment.
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