Targeting metabotropic glutamate receptor 4 for cancer immunotherapy.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34890233.
- Also identified by DOI 10.1126/sciadv.abj4226 and PMC identifier 8664261.
- Licence recorded as CC BY-NC.
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Abstract
In this study, we report a novel role of metabotropic glutamate receptor 4 (GRM4) in suppressing antitumor immunity. We revealed in three murine syngeneic tumor models (B16, MC38, and 3LL) that either genetic knockout (<i>Grm4</i><sup>−/−</sup>) or pharmacological inhibition led to significant delay in tumor growth. Mechanistically, perturbation of GRM4 resulted in a strong antitumor immunity by promoting natural killer (NK), CD4<sup>+</sup>, and CD8<sup>+</sup> T cells toward an activated, proliferative, and functional phenotype. Single-cell RNA sequencing and T cell receptor profiling further defined the clonal expansion and immune landscape changes in CD8<sup>+</sup> T cells. We further showed that <i>Grm4</i><sup>−/−</sup> intrinsically activated interferon-γ production in CD8<sup>+</sup> T cells through cyclic adenosine 3′,5′-monophosphate (cAMP)/cAMP response element binding protein–mediated pathway. Our study appears to be of clinical significance as a signature of NK<sup>high</sup>-GRM4<sup>low</sup> and CD8<sup>high</sup>-GRM4<sup>low</sup> correlated with improved survival in patients with melanoma. Targeting GRM4 represents a new approach for cancer immunotherapy.