Neurotransmitter receptor GRM4 is expressed on immune cells and involved in regulation of the EAE model of autoimmunity. In three tumor models, comparisons between male Grm4+/+ and Grm4-/- KO mice indicated that the absence of GRM4 resulted in delayed tumor growth (also observed with pharmacological GRM4 inhibition), and enhanced proliferation and activation of NK and CD8+ T cells in the TME. Synergistic antitumor effects were observed in Grm4-/- KOs in combination with ICB. GRM4-dependent effects were not observed in female mice. Improved survival in male patients with melanoma is associated with an NK (or CD8)high-GRM4low signature.
Contributed by Margot O’Toole
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 (Grm4−/−) 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+, and CD8+ 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+ T cells. We further showed that Grm4−/− intrinsically activated interferon-γ production in CD8+ 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 NKhigh-GRM4low and CD8high-GRM4low correlated with improved survival in patients with melanoma. Targeting GRM4 represents a new approach for cancer immunotherapy