The proportions of immune cells in metastatic brain tissues are lower, while macrophage infiltration is higher.
Tumor-associated macrophages () with high levels of secreted phosphoprotein 1 () may limit the activation of CD8T cells.
SPP1TAMs are associated with reduced cytokine production, contributing to immune suppression in lung cancer.
Anti-SPP1 treatment can improve CD8T cell function and increase cytokine production, countering the effects of SPP1.
SPP1 overexpression in macrophages enhances their immunosuppressive characteristics by increasing levels of CD73 and immunosuppressive cytokines like IL-10 and TGF-β.
Neutralization of SPP1 or its receptor A2AR restores CD8⁺ T cell activity, suggesting potential therapeutic strategies.
Simplified
BACKGROUND: Metastatic lung carcinoma poses considerable treatment difficulties. It exhibits cellular characteristics that differ from those of early-stage cancer. Immunotherapy demonstrates enhanced hope for patients with advanced and metastatic lung cancer. Tumor-associated macrophages () may be a contributing factor that diminishes the effectiveness of immunotherapy. Secreted phosphoprotein 1 ()TAMs are considered to possess immunosuppressive characteristics, as their interaction with CD8T lymphocytes results in the exhaustion of these cells. + +
METHODS: We analyzed single-cell RNA sequencing datasets of lung cancer metastases in order to examine the development of brain metastatic tumors. Furthermore, the cell-cell interactions between SPP1TAM cells and CD8T cells within primary and brain metastatic cancers were systematically compared. Additionally, we utilized a flow cytometer and immunofluorescence to demonstrate how SPP1 affects the function of CD8T cells. In vitro, we generated SPP1-overexpressing macrophages and performed qPCR, Western blot, and co-culture assays with or without anti-SPP1 or anti-A2AR treatment to evaluate immunosuppressive effects. + + +
RESULTS: The results demonstrated that the proportions of immune cells in metastatic brain tissues are lower, while the infiltration of macrophages is higher. SPP1TAMs contribute to immune suppression in lung cancer by limiting the activation of CD8T cells and cytokine production. Anti-SPP1 treatment positively impacts CD8T cell function, counteracting SPP1-induced dysfunction and facilitating the production of cytokines. SPP1 overexpression in macrophages enhanced their immunosuppressive phenotype by upregulating CD73 and cytokines such as IL-10 and TGF-β, leading to impaired CD8⁺ T cell function via A2AR signaling; notably, neutralization of SPP1 or A2AR successfully restored CD8⁺ T cell activity. + + +
CONCLUSIONS: Our findings characterize the immunological environment of both primary and metastatic lung cancer, highlighting SPP1-mediated immune suppression as a potential therapeutic target to restore T cell responses. Preclinical data demonstrate that Anti-SPP1 antibodies can reverse T cell exhaustion and enhance immune responses in lung cancer.
Key numbers
9%
T Cell Proportion Reduction
T cell proportion in metastatic brain tissue vs. primary tumor tissue.
0.5 µg
Treatment Effect
Recombinant protein dose affecting T cell cytokine production.
59%
+ TAM Prevalence
+ in metastatic brain tissues vs. primary tumors.
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Declarations. Conflict of interests: The authors declare that they have no competing interests. Ethical approval: This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University, China, Ethics approval number: (2024-KY-0618–004).
