Bilemjian Vrouyr, Vlaming Martijn R, Álvarez Freile Jimena, Huls Gerwin, De Bruyn Marco, Bremer Edwin
Department of Hematology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
Cancers (Basel). 2022 Jun 28;14(13):3164. doi: 10.3390/cancers14133164.
High levels of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) are associated with a survival benefit in various cancer types and the targeted (re)activation of TILs is an attractive therapeutic anti-cancer approach that yields curative responses. However, current T cell targeting strategies directed at known immune checkpoints have not increased objective response rates for all cancer types, including for epithelial ovarian cancer (EOC). For this reason, the identification of new immune checkpoints that regulate T cell immunity remains of great interest. One yet largely uninvestigated checkpoint of potential interest is the G protein-coupled receptor 56 (GPR56), which belongs to the adhesion GPCR family. GPR56 was originally reported to function in cerebral cortical development and in anti-depressant response, but also in cancer. Recently, GPR56 was identified as an inhibitory receptor expressed on human NK cells that by cis-interaction with the tetraspanin CD81 attenuated the cytotoxic activity of NK cells. This NK cell checkpoint could be blocked by an GPR56 antibody, leading to increased cytotoxicity. Interestingly, GPR56 expression has also been reported on cytokine producing memory CD8 T lymphocytes and may thus represent a T cell checkpoint as well. Here, GPR56 mRNA expression was characterized in the context of TILs, with GPR56 expression being detected predominantly in tumor infiltrating CD8 T cells with a cytotoxic and (pre-)exhausted phenotype. In accordance with this mRNA profile, TILs from ovarian cancer patients expressed GPR56 primarily within the effector memory and central memory T cell subsets. On T cells from healthy donors the expression was limited to effector memory and terminally differentiated T cells. Notably, GPR56 expression further increased on TILs upon T cell receptor (TCR)-mediated stimulation in co-cultures with cancer cells, whereas GPR56 expression on healthy primary human T cells did not. Further, the ectopic expression of GPR56 significantly reduced the migration of GPR56-positive T cells. Taken together, GPR56 is a potential immune-checkpoint in EOC found on (pre-)exhausted CD8 TILs that may regulate migratory behavior.
肿瘤微环境（TME）中高水平的肿瘤浸润淋巴细胞（TILs）与多种癌症类型的生存获益相关，靶向（再）激活TILs是一种有吸引力的抗癌治疗方法，可产生治愈性反应。然而，目前针对已知免疫检查点的T细胞靶向策略并未提高所有癌症类型的客观缓解率，包括上皮性卵巢癌（EOC）。因此，鉴定调节T细胞免疫的新免疫检查点仍然备受关注。一个潜在的、尚未得到充分研究的检查点是G蛋白偶联受体56（GPR56），它属于粘附GPCR家族。GPR56最初被报道在大脑皮质发育、抗抑郁反应以及癌症中发挥作用。最近，GPR56被鉴定为在人类NK细胞上表达的抑制性受体，通过与四跨膜蛋白CD81的顺式相互作用减弱NK细胞的细胞毒性活性。这种NK细胞检查点可以被GPR56抗体阻断，从而导致细胞毒性增加。有趣的是，也有报道称GPR56在产生细胞因子的记忆性CD8 T淋巴细胞上表达，因此它也可能代表一种T细胞检查点。在此，在TILs的背景下对GPR56 mRNA表达进行了表征，发现GPR56表达主要在具有细胞毒性和（预）耗竭表型的肿瘤浸润CD8 T细胞中检测到。与这种mRNA谱一致，卵巢癌患者的TILs主要在效应记忆和中枢记忆T细胞亚群中表达GPR56。在健康供体的T细胞上，表达仅限于效应记忆和终末分化的T细胞。值得注意的是，在与癌细胞共培养时，经T细胞受体（TCR）介导的刺激后，TILs上的GPR56表达进一步增加，而健康原代人T细胞上的GPR56表达则没有增加。此外，GPR56的异位表达显著降低了GPR56阳性T细胞的迁移。综上所述，GPR56是在（预）耗竭的CD8 TILs上发现的EOC中的一种潜在免疫检查点，可能调节迁移行为。
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