AI Article Synopsis

  • Hyperactivated PRMT5 is linked to cancer and its inhibitors could enhance immune responses, but broad inhibition negatively affects immune cells, necessitating targeted strategies for tumor treatments, especially in cancers lacking MMAP.
  • Researchers designed isogenic tumor lines using CRISPR to test the effects of PRMT5 inhibitors GSK3326595 and MRTX1719, focusing on their impact on tumor and T cell behavior.
  • The study found that MRTX1719 effectively inhibits PRMT5 specifically in MTAP-loss tumors, reduces immune resistance, and enhances T cell activity, making it promising when combined with immune checkpoint therapies like anti-PD-1 for cancer treatment.

Article Abstract

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 and . 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418539PMC
http://dx.doi.org/10.1136/jitc-2024-009600DOI Listing

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