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Isolation of Circulating Tumor Cells in an Orthotopic Mouse Model of Colorectal Cancer
Published on: July 18, 2017
PD-1 inhibitors dependent CD8+ T cells inhibit mouse colon cancer cell metastasis
Chang E Gao1,2, Ming Zhang3, Qian Song4
1The First Affiliated Hospital of Kunming Medical University, Department of Medical Oncology, Kunming, Yunnan 650031, People's Republic of China.
Background:
Colon cancer is a common digestive tract malignancy which ranks as the third leading cause of cancer death worldwide. A current focus of anti-cancer research is harnessing the patient's own immune system for therapy. Programmed cell death protein 1 (PD-1), an immune suppressor, is upregulated in various activated immune cells, such as T cells, and in viral infections and tumors.
Purpose:
The objective of this study was to investigate the function of PD-1 inhibitor on the metastasisi of mouse colon cancer cells.
Patients And Methods:
In the present study, we established an in situ colon cancer mouse model using the CT26 cell line. Hematoxylin-eosin (HE) staining was performed to detect colon cancer cell metastasis. The levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12) in serum and mesenteric lymph nodes (MLNs) were detected by Enzyme-linked immunosorbent assay (ELISA). CD44high CD62Llow memory T cells, CD4+ FoxP3+ regulatory T cells, and IFN-γ and TNF-α levels in MLNs and spleen were detected by flow cytometry (FCM).
Results:
We found that anti-PD-1 therapy inhibited colon cancer cells metastasis to the small intestine, liver, and lung, and lengthened the survival time of mice. However, the depletion of CD8 suppressed the activity of anti-PD-1 antibodies. In response to anti-PD-1 immunotherapy, the levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-12 (IL-12) in serum and mesenteric lymph nodes (MLNs) were significantly increased, while IL-6, IL-17, and transforming growth factor-β (TGF-β) were decreased. CD8 depletion had the opposite effect. In addition, anti-PD-1 treatment significantly increased CD44high CD62Llow memory T cells, decreased CD4+ FoxP3+ regulatory T cells, and increased IFN-γ and TNF-α levels in MLNs and spleen. Furthermore, anti-PD-1 treatment cannot exert these roles when CD8 is depleted.
Conclusion:
These results suggest that PD-1 inhibitors rely on CD8+ T cells to exert anti-tumor immunity in colon cancer.
Insights
Anti-PD-1 therapy effectively inhibits colon cancer metastasis and improves survival by boosting immune responses. This immunotherapy
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Colon cancer is a leading cause of cancer death globally.
- Harnessing the patient's immune system is a key anti-cancer strategy.
- Programmed cell death protein 1 (PD-1) is an immune suppressor found on activated immune cells and in tumors.
Purpose of the Study:
- To investigate the efficacy of PD-1 inhibitors in reducing colon cancer metastasis in a mouse model.
- To understand the immunological mechanisms underlying PD-1 inhibitor activity.
Main Methods:
- An in situ colon cancer mouse model (CT26 cell line) was established.
- Hematoxylin-eosin staining assessed metastasis.
- ELISA measured cytokine levels (IFN-γ, TNF-α, IL-12).
- Flow cytometry analyzed T cell populations (CD44high CD62Llow memory T cells, CD4+ FoxP3+ regulatory T cells) and cytokine expression.
Main Results:
- Anti-PD-1 therapy inhibited metastasis to the small intestine, liver, and lung, and increased survival.
- Immune responses were modulated: increased IFN-γ, TNF-α, IL-12; decreased IL-6, IL-17, TGF-β.
- PD-1 inhibition enhanced CD44high CD62Llow memory T cells and reduced CD4+ FoxP3+ regulatory T cells.
- CD8+ T cell depletion abrogated the anti-tumor effects of anti-PD-1 therapy.
Conclusions:
- PD-1 inhibitors are effective against colon cancer metastasis.
- The anti-tumor activity of PD-1 inhibitors is dependent on CD8+ T cells.
- PD-1 inhibition modulates the tumor microenvironment to promote anti-tumor immunity.
