Achieving Synergistic Antitumor Activity by Dual Blocking of CCR1 and CXCR2 Expression in Myeloid Cells

Background Introduction

Colorectal Cancer (CRC) poses a global health crisis, with its incidence and mortality rates rapidly rising in recent years. Over the past 15 years, the mortality rate of CRC has increased by more than 30%, and it is expected to increase by another 25% in the next decade. Despite significant advancements in surgery, radiotherapy, chemotherapy, and molecular targeted drugs, distal metastasis, particularly liver metastasis, remains a crucial factor leading to poor prognosis in CRC, affecting at least one-third of patients.

The Tumor Microenvironment (TME) plays a critical role in tumor progression and metastasis. The TME includes cancer cells, immune cells, stromal cells, and various host cells (such as macrophages, fibroblasts, and mesenchymal stem cells). These components engage in extensive crosstalk through signaling pathways such as TGF-β, TNF, and NF-κB, driving tumor growth, invasion, angiogenesis, immune evasion, and metastasis. Bone Marrow-Derived Cells (BMDCs), including neutrophils, monocytes, and Myeloid-Derived Suppressor Cells (MDSCs), have increasingly been recognized for their role in tumor development. BMDCs contribute to tumor growth, angiogenesis, epithelial-mesenchymal transition, and metastasis, making them potential therapeutic targets. Neutrophils, especially Tumor-Associated Neutrophils (TANs), have been identified as significant promoters of cancer progression.

Chemokines regulate the infiltration and localization of immune cells in the tumor microenvironment via their receptors. Studies have shown that aberrant TGFB signaling in CRC cells leads to increased expression of murine CCL9 or human CCL15, attracting CCR1+ myeloid cells to the tumor, thereby promoting primary tumor growth and metastasis. A recent publication further explores the therapeutic effect of dual blocking of CCR1 and CXCR2 receptors in myeloid cells for CRC treatment.

Research Source

This study was published in the “British Journal of Cancer” in 2024, with authors including Hideyuki Masui and Kenji Kawada. The research was principally conducted by the Graduate School of Medicine and affiliated research institutions of Kyoto University, in collaboration with the Rogel Cancer Center at the University of Michigan, USA. The study focused on the impact of dual blocking of CCR1 and CXCR2 expression in myeloid cells on colorectal cancer.

Research Process

The study utilized two novel colorectal cancer mouse models: a transplanted tumor model and a liver metastasis model. The research team first generated double-gene knockout mice for CCR1 and CXCR2 (ccr1−/−cxcr2−/−) and conducted bone marrow (BM) transplantation experiments, rebuilding lethally irradiated wild-type mice with BM from wild-type, CCR1−/−, CXCR2−/−, or ccr1−/−cxcr2−/− mice.

1. Mouse Models and Cell Line Culture: Experiments were conducted using both compound knockout and wild-type mice. Colorectal cancer cells and their transgenic cell lines were cultured using various methods for further experimentation.

2. Transplanted Tumor Model: Colorectal cancer cells were implanted under the back skin of mice, and tumor growth was monitored to assess the impact of gene knockout or antibody intervention on tumor progression.

3. Experimental Liver Metastasis Model: Colorectal cancer cells were injected into the spleen hilum of mice, and metastasis was monitored via bioluminescent imaging.

4. Gene Analysis and Experimental Methods: Techniques such as PCR, flow cytometry, and immunohistochemistry were used to confirm gene knockout effects and cell accumulation.

Main Results

1. Expression of Chemokines CXCL and CCL in CRCs and Prognosis: Data showed that chemokines CXCL1, CXCL8, and CCL15 were upregulated in colorectal cancer tissues, and high serum levels of these chemokines were correlated with poor patient prognosis.

2. Dual Blockade of CCR1 and CXCR2 Inhibiting Myeloid Cell Accumulation and Tumor Progression: In the ccr1−/−cxcr2−/− mouse model, myeloid cell accumulation was significantly reduced, and tumor growth and metastasis were notably inhibited. Bone marrow transplantation experiments further confirmed these results, as wild-type mice transplanted with ccr1−/−cxcr2−/− bone marrow displayed significant antitumor activity with smaller tumor volumes and reduced liver metastasis.

3. Immune Cell Infiltration: Immunohistochemical analysis showed a significant increase in CD8+ T cells in the double-gene knockout mice, while Ly6G+ neutrophils, FOXP3+ Treg cells, and CD31+ endothelial cells decreased, indicating that dual blockade treatment enhanced antitumor immune responses.

4. Synergistic Effect of Anti-CCR1 Monoclonal Antibody and CXCR2 Knockout: The study also tested a novel neutralizing anti-CCR1 monoclonal antibody, KM5908. Results showed that when KM5908 was used in conjunction with CXCR2 knockout, there was a synergistic effect, further inhibiting tumor growth and metastasis.

Conclusion and Significance

This study discovered that simultaneous blocking of CCR1 and CXCR2 pathways can significantly inhibit colorectal cancer progression and liver metastasis. This strategy may have significant scientific value and clinical application prospects. The confirmed synergistic effects suggest that combined use of CCR1 and CXCR2 inhibitors could play an important role in future CRC treatments.

Highlights and Innovations

1. Use of Double-Gene Knockout Mouse Model: This is the first study in cancer research to use ccr1−/−cxcr2−/− double-gene knockout mice, revealing the synergistic inhibitory effect of dual blocking CCR1 and CXCR2 on myeloid cell accumulation and tumor progression.

2. Novel Therapeutic Strategy: The study demonstrated the potential of combined treatment with anti-CCR1 monoclonal antibody and CXCR2 inhibitors, providing a new approach for CRC treatment, which has important implications for future cancer treatment research.

3. Clear Mechanistic Pathway: The study revealed that dual blocking of inflammation-related chemokine receptors can effectively regulate the immune microenvironment, enhancing antitumor immune responses and reducing the potential for inflammation to promote tumor cell proliferation and metastasis.

This study provides a solid scientific basis for the future clinical development of novel anticancer therapies. While the current results are exciting, further clinical trials are needed to validate these findings and explore potential treatment methods and strategies in greater depth.