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Modeling Oral-Esophageal Squamous Cell Carcinoma in 3D Organoids
Published on: December 23, 2022
Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1+ TAM
Bin Li1,2, Tie-Niu Song3, Fu-Rong Wang4,5
1Department of Thoracic Surgery, Lanzhou University Second Hospital, Lanzhou University Second Clinical Medical College, Lanzhou University, 730030, Lanzhou, China. dr.leebin@outlook.com.
Abstract:
Macrophages constitute one of the most common components of immune cells, which penetrate tumors and they have a key role in tumor prognosis. Here, we identified an unrecognized macrophage subpopulation, which favors tumorigenesis. These macrophages express programmed cell death protein 1 (PD1) in a constitutive manner and accumulates in esophageal squamous cell carcinoma (ESCC) in advanced stage of the disease and is negatively associated with the survival of ESCC patients. The PD1+ tumor-associated macrophages (PD1+ TAMs) displayed surface pattern and function akin to M2: a substantial enhancement in CD206 and IL-10 expression; a specific reduction in HLA-DR, CD64, and IL-12 expression; and a significant increase in the ability to inhibit CD8+ T-cell proliferation. Triggering of PD1 signal is effective in increasing PD1+ TAM function. Moreover, exosomal HMGB1 obtained from tumors are efficient in triggering differentiation of monocytes into PD1+ TAMs, which display phenotypic and functional properties of M2. Overall, our work is the first finding to confirm that exosomal HMGB1 obtained from ESCC can successfully trigger clonal expansion of PD1+ TAM. Further, as the macrophages exhibit an M2-like surface profile and function, thereby creating conditions for development of ESCC. Thus, effective methods of treatment include combining immunotherapy with targeting PD1+ TAMs and tumor-derived exosomal HMGB1 to resuscitate immune function in individuals suffering from ESCC.
Insights
Researchers discovered a new type of tumor-associated macrophage (TAM) that promotes esophageal cancer. These PD1+ TAMs, driven by exosomal HMGB1, suppress anti-tumor immunity, suggesting novel therapeutic targets for esophageal squamous cell carcinoma (ESCC).
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Macrophages are key immune cells in tumors, influencing prognosis.
- Tumor-associated macrophages (TAMs) play a critical role in cancer progression.
- Understanding macrophage subpopulations is crucial for developing effective cancer therapies.
Purpose of the Study:
- To identify and characterize novel macrophage subpopulations involved in tumorigenesis.
- To investigate the role of programmed cell death protein 1 (PD1) expressing macrophages in esophageal squamous cell carcinoma (ESCC).
- To explore the mechanism by which tumor-derived factors influence macrophage differentiation and function.
Main Methods:
- Identification of a PD1-expressing macrophage subpopulation in ESCC.
- Analysis of surface markers (CD206, HLA-DR, CD64) and cytokine expression (IL-10, IL-12) of PD1+ TAMs.
- Assessment of PD1+ TAMs' effect on CD8+ T-cell proliferation.
- Investigation of exosomal HMGB1's role in inducing PD1+ TAM differentiation.
Main Results:
- A novel PD1+ TAM subpopulation was identified, accumulating in advanced ESCC and associated with poor patient survival.
- PD1+ TAMs exhibit M2-like characteristics, including enhanced CD206 and IL-10, reduced HLA-DR and IL-12, and suppressed CD8+ T-cell proliferation.
- Exosomal HMGB1 from tumors effectively differentiates monocytes into PD1+ TAMs with M2-like functions.
- PD1 signaling activation enhances PD1+ TAM function.
Conclusions:
- Exosomal HMGB1 from ESCC drives the expansion of immunosuppressive PD1+ TAMs.
- These M2-like PD1+ TAMs create a tumor-promoting microenvironment in ESCC.
- Combining immunotherapy with targeting PD1+ TAMs and exosomal HMGB1 offers a promising therapeutic strategy for ESCC.
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