Wei Xiawei's team from Sichuan University discovers a potential target for the treatment of lung cancer

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The drug resistance and severe side effects of iNature chemotherapeutics have led to a low survival rate for lung cancer patients.

The CXCLs/CXCR2 axis plays an important role in the progression of cancers including lung cancer.

However, the specific anti-cancer mechanism targeting CXCR2 remains unclear.

On April 4, 2021, Wei Xiawei’s team from Sichuan University published an online research paper titled "Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin" in Molecular Cancer (IF=15.
30).
This research is in clinical lung adenocarcinoma Immunohistochemical analysis of CXCR2 was performed on the microarrays of tumor tissues from patients with lung squamous cell carcinoma.

The study found that the expression of CXCR2 in human lung cancer stroma and tumor cells is elevated, which is related to the prognosis of patients.

Inhibition of CXCR2 can promote lung cancer cell apoptosis, senescence, epithelial-mesenchymal transition (EMT) and anti-proliferation.

In vivo studies have shown that tumor-associated neutrophils (TANs) significantly penetrate into tumor tissues in mouse models, and their CXCLs/CXCR2 signaling and inhibitory molecules are up-regulated, including Arg-1 and TGF-β.

SB225002, a selective CXCR2 inhibitor, shows promising therapeutic effects, and by promoting the activation of CD8 + T cells, it significantly reduces the infiltration of neutrophils and enhances the activity of anti-tumor T cells.

At the same time, the blockade of CXCR2 can enhance the therapeutic effect of cisplatin by regulating the infiltration of neutrophils.

In summary, the findings of this study validate the therapeutic effect of targeting CXCR2 in lung cancer and reveal the underlying mechanism of CXCR2 antagonists to increase the sensitivity of chemotherapeutics.

In addition, on July 29, 2020, Wei Xiawei, Lu Guangwen, and Zhang Kang of the Faculty of Medicine of Macau University of Science and Technology jointly published the title "A vaccine targeting the RBD of the S protein of SARS" in Nature on July 29, 2020.
-CoV-2 induces protective immunity" research paper, the study found that the recombinant vaccine containing S-RBD residues 319-545 can be used in immunized mice, rabbits and non-human primates 7 or 14 days after a single dose Induces effective functional antibody responses in animal-like animals (rhesus monkeys).

The serum of immunized animals blocked the binding of RBD to ACE2 expressed on the cell surface in vitro, and neutralized the infection of SARS-CoV-2 pseudovirus and SARS-CoV-2 live virus.

Importantly, the vaccine also provides protection from SARS-CoV-2 attacks in non-human primates.

In mice and monkeys vaccinated with RBD immune serum, no adverse reactions such as antibody-dependent pneumonia enhancement or acceleration of pneumonia were observed.

Compared with the whole extracellular protein part (ECD), S1-subunit protein or S2-subunit protein and other parts of S protein, the virus neutralization activity of the recombinant RBD protein vaccine is much higher, so the recombinant RBD protein vaccine is As the best vaccine choice for immunogen.

Elevated RBD-specific antibodies were also found in the serum of COVID-19 patients.

Several immunization pathways and CD4 T lymphocytes are involved in the induction of vaccine antibody responses.

The findings highlight the importance of the RBD domain in SARS-CoV-2 vaccine design and provide a basis for the development of protective vaccines by inducing antibodies against the RBD domain (click to read).

Lung cancer is the leading cause of mortality related to malignant tumors worldwide.

More importantly, it has surpassed breast cancer and has become the leading cause of cancer deaths.

Due to air pollution, despite the low smoking rate, the incidence of lung cancer among Chinese women is still higher than that of women in some European countries.

Data show that among non-smokers between 30 and 50 years old, the incidence of lung cancer is increasing rapidly.

Among all lung cancer cases, non-small cell lung cancer (NSCLC) accounts for more than 85%.

Despite the efforts made in the treatment strategy, the survival rate of NSCLC patients is still unsatisfactory, and the 5-year survival rate is about 17%.

The drug resistance during treatment is one of the reasons for the low survival rate of lung cancer patients.

Platinum-based therapy is the first-line treatment for lung cancer chemotherapy.

Currently, the platinum compounds used for NSCLC patients are cisplatin and carboplatin.

Their anti-tumor activity is mainly based on the formation of platinum-DNA adducts, which can induce DNA damage and cancer cell apoptosis.

For patients with resectable NSCLC, surgical resection after (neo-adjuvant) or platinum-adjuvant drugs is the standard treatment.

The drug resistance and obvious side effects of platinum drugs make combination therapy and targeted therapy a promising strategy.

In recent decades, small molecule targeted therapies, such as receptor tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors, have provided new ways to justify the treatment of NSCLC patients.

The development of immune checkpoint blockade (ICB) therapy has completely changed the treatment of advanced NSCLC.

Currently, the U.
S.
Food and Drug Administration (FDA) has approved a variety of immune checkpoint inhibitors for the treatment of NSCLC, including the PD-1 inhibitor Nivolumab, Pembrolizumab, and the PD-L1 inhibitor Atezolizumab and Durvalumab.

However, despite the application of these new treatment strategies, multiple immune resistance mechanisms in the tumor microenvironment have led to poor therapeutic effects.

The tumor microenvironment is composed of various non-malignant cells (such as leukocytes, fibroblasts and endothelial cells) and non-cellular components (such as cytokines and chemokines).

Macrophages and neutrophils are two types of myeloid cells that are abundant in the tumor microenvironment.

Tumor-related immunosuppressive bone marrow cells are closely related to poor prognosis and ineffective treatment.

Tumor-associated neutrophils (TANs) are polarized by many factors in the tumor microenvironment, such as hypoxia and cytokines.

TANs are polarized into N2 type after exposure to TGF-β, while IFN-γ can convert TANs to N1 type.

Recent studies have proven that targeting tumor-associated immunosuppressive myeloid cells can enhance anti-tumor activity against lung cancer.

Since the first CXC chemokine IL-8 was discovered in the 1980s, there have been many studies on IL-8 and its receptor.

Two IL-8 receptors were discovered: IL-8 RA and IL-8 RB, also known as CXCR1 and CXCR2.

CXCR2 and CXCR1 share 77% sequence homology, and they both bind to IL-8 with similar affinity (Kd approximately 4 nM).

However, CXCR1 only binds to CXCL6 and CXCL8 in humans, and lacks the orthologue of CXCL8 in mice.
CXCR1 is activated by CXCL1 and CXCL6, which indicates that CXCR2 interacts with more ELR + chemokines and has Higher affinity, and plays a more important role in cell chemotaxis.

CXCR2 is a typical G protein coupled receptor.

CXCR2 and its ligands show strong chemotaxis of neutrophils or myeloid suppressor cells (MDSC), and are related to tumor angiogenesis, progression and chemoresistance.

In lung adenocarcinoma, CXCR2 is a poor prognostic marker, and its expression is related to tumor invasion and metastasis.

Previous studies have proved that high levels of CXCR2 in lung cancer cells are related to smoking and poor prognosis in clinical patients.

Inhibition of CXCR2 and its ligand CXCL8 can significantly inhibit the proliferation and migration of lung cancer cells and reduce angiogenesis.

At the same time, the CXCLs/CXCR2 axis is considered to be closely related to tumor drug resistance.

These findings indicate that the CXCLs/CXCR2 axis plays a potential role in chemotherapy or radiation therapy for non-small cell lung cancer.

The study performed CXCR2 immunohistochemical analysis on microarrays of tumor tissues from patients with clinical lung adenocarcinoma and lung squamous cell carcinoma.

The study found that the expression of CXCR2 in human lung cancer stroma and tumor cells is elevated, which is related to the prognosis of patients.

Inhibition of CXCR2 can promote lung cancer cell apoptosis, senescence, epithelial-mesenchymal transition (EMT) and anti-proliferation.

In vivo studies have shown that tumor-associated neutrophils (TANs) significantly penetrate into tumor tissues in mouse models, and their CXCLs/CXCR2 signaling and inhibitory molecules are up-regulated, including Arg-1 and TGF-β.

SB225002, a selective CXCR2 inhibitor, shows promising therapeutic effects, and by promoting the activation of CD8 + T cells, it significantly reduces the infiltration of neutrophils and enhances the activity of anti-tumor T cells.

At the same time, the blockade of CXCR2 can enhance the therapeutic effect of cisplatin by regulating the infiltration of neutrophils.

In summary, the findings of this study validate the therapeutic effect of targeting CXCR2 in lung cancer and reveal the underlying mechanism of CXCR2 antagonists to increase the sensitivity of chemotherapeutics.

Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01355-1