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Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

Zhuoya Wan1, Runzi Sun2, Yang-Wuyue Liu1

  • 1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.

Science Advances
|December 10, 2021
PubMed

Insights

Metabotropic glutamate receptor 4 (GRM4) suppresses antitumor immunity. Inhibiting GRM4 enhances natural killer and T cell responses, delaying tumor growth and improving patient survival, offering a new cancer immunotherapy strategy.

Area of Science:

  • Immunology
  • Oncology
  • Neuroscience

Background:

  • Metabotropic glutamate receptor 4 (GRM4) is implicated in various physiological processes.
  • Its role in cancer immunity remains largely unexplored.

Purpose of the Study:

  • To investigate the role of GRM4 in antitumor immunity.
  • To explore GRM4 as a potential target for cancer immunotherapy.

Main Methods:

  • Murine syngeneic tumor models (B16, MC38, 3LL) with genetic knockout (Grm4-/-) or pharmacological inhibition of GRM4.
  • Flow cytometry, single-cell RNA sequencing, T cell receptor profiling.
  • Analysis of immune cell phenotypes, proliferation, and cytokine production (interferon-gamma).

Main Results:

  • Genetic or pharmacological GRM4 inhibition significantly delayed tumor growth in all models.
  • GRM4 perturbation enhanced natural killer (NK) and CD4+/CD8+ T cell responses, promoting activation and proliferation.
  • GRM4 knockout activated interferon-gamma production in CD8+ T cells via the cAMP/CREB pathway.
  • A NKhigh-GRM4low and CD8high-GRM4low signature correlated with improved melanoma patient survival.

Conclusions:

  • GRM4 plays a novel role in suppressing antitumor immunity.
  • Targeting GRM4 enhances anti-tumor immune responses and holds clinical significance for cancer immunotherapy, particularly in melanoma.

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