Dendritic cell-targeting chemokines inhibit colorectal cancer progression
Pengkun Yuan1,2,3, Yunyi Zhou1,2, Zhixue Wang1,2
1School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China.
Aim:
Recent progress in cancer immunotherapy has shown its promise and prompted researchers to develop novel therapeutic strategies. Dendritic cells (DCs) are professional antigen-presenting cells crucial for initiating adaptive anti-tumor immunity, therefore a promising target for cancer treatment. Here, anti-tumor activities of DC-targeting chemokines were explored in murine colorectal tumor models.
Methods:
The correlation of chemokine messenger RNA (mRNA) expression with DC markers was analyzed using The Cancer Genome Atlas (TCGA) dataset. Murine colorectal tumor cell lines (CT26 and MC38) stably overexpressing mouse C-C motif chemokine ligand 3 (CCL3), CCL19, CCL21, and X-C motif chemokine ligand 1 (XCL1) were established by lentiviral transduction. The effect of chemokines on tumor cell proliferation/survival was evaluated in vitro by cell counting kit-8 (CCK-8) assay and colony formation assay. Syngeneic subcutaneous tumor models were used to study the effects of these chemokines on tumor growth. Ki-67 expression in tumors was examined by immunohistochemistry. Immune cells in the tumor microenvironment (TME) and lymph nodes were analyzed by flow cytometry.
Results:
Expression of the four chemokines was positively correlated with the two DC markers [integrin alpha X (ITGAX) and CLEC9A] in human colorectal tumor samples. Tumoral overexpression of DC-targeting chemokines had little or no effect on tumor cell proliferation/survival in vitro while significantly suppressing tumor growth in vivo. Fluorescence-activated cell sorting (FACS) analysis showed that CCL19, CCL21, and XCL1 boosted the ratios of DCs and T cells in CD45+ leukocytes while CCL3 increased the percentage of CD45+ leukocytes in total cells in MC38 tumor. XCL1 had an additional positive effect on antigen uptake by DCs in the TME and antigen transfer to tumor-draining lymph nodes.
Conclusions:
CCL3, CCL19, CCL21, and XCL1 exhibited potent anti-tumor activities in vivo, although they might differentially regulate immune cells in the TME and antigen transfer to lymph nodes.
Insights
DC-targeting chemokines like CCL3, CCL19, CCL21, and XCL1 show potent anti-tumor activity in colorectal cancer models. These chemokines suppress tumor growth in vivo by modulating immune cells in the tumor microenvironment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Cancer immunotherapy, particularly using dendritic cells (DCs), is a promising therapeutic strategy.
- DCs are key antigen-presenting cells for initiating adaptive anti-tumor immunity.
- Targeting DCs with specific chemokines offers a novel approach for cancer treatment.
Purpose of the Study:
- To explore the anti-tumor activities of DC-targeting chemokines (CCL3, CCL19, CCL21, XCL1) in murine colorectal tumor models.
- To investigate the correlation between chemokine expression and DC markers in human colorectal cancer.
- To analyze the effects of these chemokines on immune cell populations within the tumor microenvironment and lymph nodes.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) dataset for chemokine and DC marker correlations.
- Generation of colorectal tumor cell lines overexpressing specific chemokines via lentiviral transduction.
- In vitro assays (CCK-8, colony formation) to assess tumor cell proliferation and survival.
- In vivo studies using syngeneic tumor models to evaluate tumor growth inhibition.
- Immunohistochemistry for Ki-67 expression and flow cytometry for immune cell analysis in the tumor microenvironment and lymph nodes.
Main Results:
- Positive correlation observed between the expression of CCL3, CCL19, CCL21, XCL1 and DC markers (ITGAX, CLEC9A) in human colorectal tumors.
- Tumoral overexpression of these chemokines showed minimal impact on tumor cell proliferation in vitro but significantly suppressed tumor growth in vivo.
- Flow cytometry revealed that CCL19, CCL21, and XCL1 increased DC and T cell ratios, while CCL3 enhanced overall CD45+ leukocyte infiltration.
- XCL1 demonstrated additional benefits in promoting DC antigen uptake and transfer to tumor-draining lymph nodes.
Conclusions:
- CCL3, CCL19, CCL21, and XCL1 exhibit significant in vivo anti-tumor effects in colorectal cancer models.
- These chemokines differentially modulate immune cell populations within the tumor microenvironment.
- Chemokines play a role in regulating immune cell infiltration and antigen presentation, impacting anti-tumor immunity.
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