Targeting metabotropic glutamate receptor 4 for cancer immunotherapy.
Targeting metabotropic glutamate receptor 4 for cancer immunotherapy.
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DOI：
10.1126/sciadv.abj4226
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发表时间：
2021-12-10
期刊：
影响因子：
13.6
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Wan Z;Sun R;Liu YW;Li S;Sun J;Li J;Zhu J;Moharil P;Zhang B;Ren P;Ren G;Zhang M;Ma X;Dai S;Yang D;Lu B;Li S
免疫细胞衍生的GRM4负向调节抗肿瘤免疫反应。在本研究中，我们报道了代谢型谷氨酸受体4(GRM4)在抑制抗肿瘤免疫中的新作用。我们在三个小鼠同基因肿瘤模型(B16、MC38和3LL)中发现，基因敲除(Grm4−/−)或药物抑制都会导致肿瘤生长显著延迟。从机制上讲，GRM4的干扰通过促进自然杀伤细胞(NK)、CD4+和CD8+T细胞向激活的、增殖的和功能性的表型转变，从而导致强大的抗肿瘤免疫。单细胞RNA测序和T细胞受体分析进一步确定了CD8+T细胞的克隆性增殖和免疫格局的变化。我们进一步证明，Grm4−/−通过环腺苷3‘，5’-单磷酸(CAMP)/cAMP反应元件结合蛋白介导的途径内在地激活CD8+T细胞产生干扰素-γ。我们的研究似乎具有临床意义，因为NKHigh-GRM4low和CD8High-GRM4low与提高黑色素瘤患者的存活率相关。靶向GRM4代表了癌症免疫治疗的一种新方法。
Immune cell–derived GRM4 negatively modulates antitumor immune response. 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.
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