乳酸受体抑制剂有助于乳腺癌免疫治疗

　　GPR81是乳酸的鸟苷酸结合蛋白偶联受体，高表达于乳腺癌，并且具有自分泌作用，可以通过肿瘤细胞来源的乳酸促进肿瘤生长。不过，乳酸受体GPR81促进乳腺癌生长的具体机制及其靶点尚不明确。

　　2020年2月19日，英国《自然》旗下《肿瘤基因》在线发表美国德克萨斯理工大学的研究报告，探讨了乳酸受体GPR81促进乳腺癌生长的具体机制及其靶点。

　　首先，该研究通过小鼠乳腺多瘤病毒中间T抗原转基因（MMTV-PyMT-Tg）模型，证实GPR81基因缺失可以抑制乳腺癌的生长。随后，该研究利用同基因移植模型，对乳腺脂肪植入GPR81阴性小鼠乳腺癌AT-3细胞的野生型小鼠与GPR81基因缺失小鼠肿瘤生长进行监测。

　　结果，GPR81基因缺失小鼠与野生型小鼠相比，肿瘤生长受到显著抑制，肿瘤浸润T淋巴细胞和主要组织相容性复合体II高表达免疫细胞显著较多。

　　肿瘤核糖核酸（RNA）序列分析表明，肿瘤微环境的免疫细胞和抗原呈递参与了依赖于GPR81的肿瘤生长。呈递抗原的肿瘤微环境树突状细胞可表达GPR81，并且GPR81的活化可被受到乳酸抑制的主要组织相容性复合体II向细胞表面呈递。树突状细胞的GPR81激活，与环磷酸腺苷、白细胞介素-6、白细胞介素-12的减少密切相关。

　　因此，该研究结果表明，肿瘤细胞来源的乳酸可以激活树突状细胞GPR81，并且阻止肿瘤特异性抗原向其他免疫细胞呈递。该旁分泌机制是对自分泌机制的补充，该机制发现乳酸通过激活肿瘤细胞GPR81可以诱导肿瘤细胞程序死亡配体PD-L1，从而为肿瘤细胞逃避免疫系统提供了有效手段，而阻断GPR81信号传导的靶向抑制剂，可以加速乳腺癌的免疫治疗。

Oncogene. 2020 Feb 19. [Epub ahead of print]

The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment.

Timothy P. Brown, Pushpak Bhattacharjee, Sabarish Ramachandran, Sathish Sivaprakasam, Bojana Ristic, Mohd Omar F. Sikder, Vadivel Ganapathy.

Texas Tech University Health Sciences Center, Lubbock, TX, USA.

GPR81 is a G-protein-coupled receptor for lactate, which is upregulated in breast cancer and plays an autocrine role to promote tumor growth by tumor cell-derived lactate. Here we asked whether lactate has any paracrine role via activation of GPR81 in cells present in tumor microenvironment to help tumor growth. First, we showed that deletion of Gpr81 suppresses breast cancer growth in a constitutive breast cancer mouse model (MMTV-PyMT-Tg). We then used a syngeneic transplant model by monitoring tumor growth from a mouse breast cancer cell line (AT-3, Gpr81-negative) implanted in mammary fat pad of wild-type mice and Gpr81-null mice. Tumor growth was suppressed in Gpr81-null mice compared with wild-type mice. There were more tumor-infiltrating T cells and MHCIIhi-immune cells in tumors from Gpr81-null mice compared with tumors from wild-type mice. RNA-seq analysis of tumors indicated involvement of immune cells and antigen presentation in Gpr81-dependent tumor growth. Antigen-presenting dendritic cells expressed Gpr81 and activation of this receptor by lactate suppressed cell-surface presentation of MHCII. Activation of Gpr81 in dendritic cells was associated with decreased cAMP, IL-6 and IL-12. These findings suggest that tumor cell-derived lactate activates GPR81 in dendritic cells and prevents presentation of tumor-specific antigens to other immune cells. This paracrine mechanism is complementary to the recently discovered autocrine mechanism in which lactate induces PD-L1 in tumor cells via activation of GPR81 in tumor cells, thus providing an effective means for tumor cells to evade immune system. As such, blockade of GPR81 signaling could boost cancer immunotherapy.

DOI: 10.1038/s41388-020-1216-5