Human γδ T lymphocytes are predominated by two major subsets, defined by the variable domain of the δ chain. Both, Vδ1 and Vδ2 T cells infiltrate in tumors and have been implicated in cancer immunosurveillance. Since the localization and distribution of tumor‐infiltrating γδ T cell subsets and their impact on survival of cancer patients are not completely defined, this review summarizes the current knowledge about this issue. Different intrinsic tumor resistance mechanisms and immunosuppressive molecules of immune cells in the tumor microenvironment have been reported to negatively influence functional properties of γδ T cell subsets. Here, we focus on selected tumor resistance mechanisms including overexpression of cyclooxygenase (COX)‐2 and indolamine‐2,3‐dioxygenase (IDO)‐1/2, regulation by tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)/TRAIL‐R4 pathway and the release of galectins. These inhibitory mechanisms play important roles in the cross‐talk of γδ T cell subsets and tumor cells, thereby influencing cytotoxicity or proliferation of γδ T cells and limiting a successful γδ T cell‐based immunotherapy. Possible future directions of a combined therapy of adoptively transferred γδ T cells together with γδ‐targeting bispecific T cell engagers and COX‐2 or IDO‐1/2 inhibitors or targeting sialoglycan‐Siglec pathways will be discussed and considered as attractive therapeutic options to overcome the immunosuppressive tumor microenvironment.

中文翻译：

---

肿瘤耐药机制及其对 γδ T 细胞活化的影响

人类 γδ T 淋巴细胞主要由两个主要亚群组成，由 δ 链的可变域定义。Vδ1 和 Vδ2 T 细胞均浸润肿瘤，并与癌症免疫监视有关。由于肿瘤浸润性 γδ T 细胞亚群的定位和分布及其对癌症患者生存的影响尚未完全确定，本综述总结了目前有关该问题的知识。据报道，肿瘤微环境中不同的内在肿瘤耐药机制和免疫细胞的免疫抑制分子会对 γδ T 细胞亚群的功能特性产生负面影响。在这里，我们关注选定的肿瘤耐药机制，包括环加氧酶 (COX)-2 和吲哚胺-2,3-双加氧酶 (IDO)-1/2 的过度表达，肿瘤坏死因子相关凋亡诱导配体（TRAIL）/TRAIL-R4通路的调节和半乳糖凝集素的释放。这些抑制机制在 γδ T 细胞亚群和肿瘤细胞的相互作用中发挥重要作用，从而影响 γδ T 细胞的细胞毒性或增殖，并限制了基于 γδ T 细胞的免疫治疗的成功。将讨论过继转移的 γδ T 细胞与 γδ 靶向双特异性 T 细胞接合剂和 COX-2 或 IDO-1/2 抑制剂或靶向唾液酸聚糖-Siglec 通路的联合治疗的可能未来方向，并将其视为具有吸引力的治疗选择来克服免疫抑制性肿瘤微环境。从而影响 γδ T 细胞的细胞毒性或增殖，并限制基于 γδ T 细胞的成功免疫疗法。将讨论过继转移的 γδ T 细胞与 γδ 靶向双特异性 T 细胞接合剂和 COX-2 或 IDO-1/2 抑制剂或靶向唾液酸聚糖-Siglec 通路的联合治疗的可能未来方向，并将其视为具有吸引力的治疗选择来克服免疫抑制性肿瘤微环境。从而影响 γδ T 细胞的细胞毒性或增殖并限制基于 γδ T 细胞的成功免疫疗法。将讨论过继转移的 γδ T 细胞与 γδ 靶向双特异性 T 细胞接合剂和 COX-2 或 IDO-1/2 抑制剂或靶向唾液酸聚糖-Siglec 通路的联合治疗的可能未来方向，并将其视为具有吸引力的治疗选择来克服免疫抑制性肿瘤微环境。