Targeting metabotropic glutamate receptor 4 for cancer immunotherapy

The complex mechanism regulating the immunosuppressive tumor
microenvironment (TME) remains poorly understood. Here,
we reported a novel role of the metabotropic glutamate
receptor-4 (GRM4) in suppressing the anti-tumor 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 and synergized with immune checkpoint
inhibitors in male mice. Mechanistically, perturbation of GRM4 resulted in
a strong anti-tumor immunity by promoting nature killer (NK),
CD4+ and CD8+ T cells towards an activated,
proliferative, and functional phenotype. Single-cell RNA-sequencing and T
Cell Receptor (TCR) profiling further defined the clonal expansion and
immune landscape changes in CD8+ T cells.
Mechanistically, Grm4-/- intrinsically activated
IFN-g production in CD8+ T cells through
cAMP/CREB-mediated pathway. Our study appears to be of clinical
significance as a signature of NKhigh-GRM4low and
CD8high-GRM4low correlated with improved survival in melanoma
patients. Therefore, targeting GRM4 could be exploited as a new approach
for cancer immunotherapy.