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Published on: December 16, 2022
Tumor-Specific EphA2 Receptor Tyrosine Kinase Inhibits Anti-Tumor Immunity by Recruiting Suppressive Myeloid
Eileen Shiuan1,2, Shan Wang3,4, Dana M Brantley-Sieders3,4
1Department of Hematology and Oncology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Background:
EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2's impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment.
Methods:
Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in murine models of non-small cell lung cancer (NSCLC).
Results:
Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrates via flow cytometry revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T-cell activation, particularly in CD8+ T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1 in RNA expression analyses.
Conclusions:
Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit the activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape.
Insights
EphA2 receptor tyrosine kinase in non-small cell lung cancer (NSCLC) promotes tumor growth by recruiting monocytes and differentiating them into immunosuppressive tumor-associated macrophages (TAMs), hindering anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- EphA2 receptor tyrosine kinase is implicated in solid tumor growth and metastasis.
- Understanding EphA2's role in immune evasion is crucial for cancer therapy.
- Investigating EphA2's impact on the tumor microenvironment is essential.
Purpose of the Study:
- To examine the effect of tumor-specific EphA2 on immune cell populations in non-small cell lung cancer (NSCLC).
- To analyze the cytokine and chemokine milieu in response to EphA2 expression in NSCLC models.
- To elucidate the mechanisms of EphA2-mediated immune evasion.
Main Methods:
- Murine models of non-small cell lung cancer (NSCLC) were utilized.
- Flow cytometry was employed to analyze immune cell infiltrates.
- RNA expression analysis was performed to assess chemokine and protein levels.
Main Results:
- EphA2 overexpression in NSCLC conferred an in vivo growth advantage.
- Tumors showed decreased natural killer and T cells, with increased myeloid cells, including tumor-associated macrophages (TAMs).
- T-cell activation decreased, PD-1 expression increased, and immunosuppressive chemokines and proteins were upregulated.
Conclusions:
- Tumor-associated EphA2 recruits monocytes and promotes their differentiation into TAMs.
- TAMs likely inhibit cytotoxic lymphocyte activation and infiltration, promoting tumor immune escape.
- Targeting EphA2 may modulate the tumor immune microenvironment.
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