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Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response
Eric Ubil1, Laura Caskey1, Alisha Holtzhausen1
1UNC Lineberger Comprehensive Cancer Center and.
Abstract:
Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-γ and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-γ inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression.
Insights
Tumor-secreted Protein S (Pros1) suppresses the immune system by inhibiting macrophage M1 cytokine expression via TAM receptors. Blocking this Pros1/TAM interaction may enhance anti-tumor immunity and improve survival.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Tyro3, Axl, Mer (TAM) receptor tyrosine kinases are known to dampen innate immune responses.
- Tumor-secreted factors can modulate the tumor microenvironment and immune cell function.
- Understanding immune suppressive mechanisms is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the role of tumor-secreted Protein S (Pros1) in modulating macrophage polarization and immune suppression.
- To elucidate the specific TAM receptors and signaling pathways involved in Pros1-mediated immune suppression.
- To evaluate the therapeutic potential of targeting the Pros1/TAM axis in cancer.
Main Methods:
- CRISPR-Cas9 gene editing to delete Pros1 in tumor cells.
- In vitro and in vivo experiments assessing macrophage M1 cytokine expression.
- Utilizing knockout (KO) mice for Mer, Tyro3, Axl, and PTP1b.
- Investigating the interaction between PTP1b and Mer in the suppressive pathway.
- Assessing immune cell infiltration and median survival in tumor-bearing mice.
- Evaluating the effect of TLR7/8 agonist treatment on tumor growth and survival.
Main Results:
- Tumor-secreted Pros1 significantly decreased macrophage M1 cytokine expression.
- CRISPR-mediated deletion of Pros1 in tumor cells abrogated immune suppression.
- Pros1's suppressive effects were mediated through Mer and Tyro3 receptors, not Axl.
- The PTP1b complexing with Mer was identified as a key component of the suppressive pathway.
- Mice with Pros1-deficient tumors exhibited increased immune infiltration and prolonged survival.
- IFN-γ stimulation upregulated Pros1 transcription and secretion, indicating cytokine responsiveness.
Conclusions:
- Tumor-derived Pros1 acts as an immune checkpoint by suppressing macrophage M1 polarization via the TAM receptor pathway.
- The Pros1/TAM/PTP1b axis represents a novel mechanism of tumor-induced immune suppression.
- Targeting the Pros1/TAM interaction offers a promising strategy to overcome tumor immune evasion and enhance immunotherapy efficacy.
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