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MTA-cooperative PRMT5 inhibitors enhance T cell-mediated antitumor activity in MTAP-loss tumors
Si Chen1, Jiakai Hou1, Roshni Jaffery1
1Biology and Biochemistry, University of Houston, Houston, Texas, USA.
Background:
Hyperactivated protein arginine methyltransferases (PRMTs) are implicated in human cancers. Inhibiting tumor intrinsic PRMT5 was reported to potentiate antitumor immune responses, highlighting the possibility of combining PRMT5 inhibitors (PRMT5i) with cancer immunotherapy. However, global suppression of PRMT5 activity impairs the effector functions of immune cells. Here, we sought to identify strategies to specifically inhibit PRMT5 activity in tumor tissues and develop effective PRMT5i-based immuno-oncology (IO) combinations for cancer treatment, particularly for methylthioadenosine phosphorylase (MTAP)-loss cancer.
Methods:
Isogeneic tumor lines with and without MTAP loss were generated by CRISPR/Cas9 knockout. The effects of two PRMT5 inhibitors (GSK3326595 and MRTX1719) were evaluated in these isogenic tumor lines and T cells in vitro and in vivo. Transcriptomic and proteomic changes in tumors and T cells were characterized in response to PRMT5i treatment. Furthermore, the efficacy of MRTX1719 in combination with immune checkpoint blockade was assessed in two syngeneic murine models with MTAP-loss tumor.
Results:
GSK3326595 significantly suppresses PRMT5 activity in tumors and T cells regardless of the MTAP status. However, MRTX1719, a methylthioadenosine-cooperative PRMT5 inhibitor, exhibits tumor-specific PRMT5 inhibition in MTAP-loss tumors with limited immunosuppressive effects. Mechanistically, transcriptomic and proteomic profiling analysis reveals that MRTX1719 successfully reduces the activation of the PI3K pathway, a well-documented immune-resistant pathway. It highlights the potential of MRTX1719 to overcome immune resistance in MTAP-loss tumors. In addition, MRTX1719 sensitizes MTAP-loss tumor cells to the killing of tumor-reactive T cells. Combining MRTX1719 and anti-PD-1 leads to superior antitumor activity in mice bearing MTAP-loss tumors.
Conclusion:
Collectively, our results provide a strong rationale and mechanistic insights for the clinical development of MRTX1719-based IO combinations in MTAP-loss tumors.
Insights
Targeted inhibition of PRMT5 (protein arginine methyltransferase 5) with MRTX1719 shows promise for cancer immunotherapy, especially in MTAP-loss tumors. This approach enhances anti-tumor immune responses without impairing T cell function, paving the way for novel immuno-oncology combinations.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Hyperactivated protein arginine methyltransferases (PRMTs) are linked to cancer development.
- Targeting PRMT5 offers potential for cancer immunotherapy, but broad inhibition can harm immune cells.
- Developing strategies for tumor-specific PRMT5 inhibition is crucial for effective immuno-oncology (IO) combinations, particularly in methylthioadenosine phosphorylase (MTAP)-loss cancers.
Purpose of the Study:
- To identify strategies for specific PRMT5 inhibition in tumor tissues.
- To develop effective PRMT5 inhibitor-based immuno-oncology combinations for cancer treatment.
- To investigate MRTX1719's efficacy in MTAP-loss tumors and its combination with immune checkpoint blockade.
Main Methods:
- Generated isogenic tumor lines with and without MTAP loss using CRISPR/Cas9.
- Evaluated PRMT5 inhibitors (GSK3326595 and MRTX1719) in vitro and in vivo.
- Analyzed transcriptomic and proteomic changes in tumors and T cells.
- Assessed the combination of MRTX1719 with anti-PD-1 in murine models of MTAP-loss tumors.
Main Results:
- MRTX1719 demonstrated tumor-specific PRMT5 inhibition in MTAP-loss tumors with minimal impact on immune cells.
- MRTX1719 reduced PI3K pathway activation, a known immune-resistance pathway.
- MRTX1719 sensitized MTAP-loss tumor cells to T cell-mediated killing.
- Combination therapy of MRTX1719 and anti-PD-1 showed superior anti-tumor activity in preclinical models.
Conclusions:
- MRTX1719 offers a promising approach for tumor-specific PRMT5 inhibition in MTAP-loss cancers.
- The findings provide a strong rationale for developing MRTX1719-based immuno-oncology combinations.
- Mechanistic insights support MRTX1719's potential to overcome immune resistance and enhance anti-tumor immunity.
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