Yan Hongxia, Zhang Ping, Kong Xue, Hou Xianglian, Zhao Li, Li Tianhang, Yuan Xiaozhou, Fu Hongjun
1 Department of Dermatology, The First People's Hospital of Jining City, Jining, China.
2 Jining Maternity and Child Health Care Hospital, Jining, China.
Tumour Biol. 2017 Apr;39(4):1010428317697554. doi: 10.1177/1010428317697554.
In malignant melanoma, tumor-associated macrophages play multiple roles in promoting tumor growth, such as inducing the transformation of melanocytes under ultraviolet irradiation, increasing angiogenesis in melanomas, and suppressing antitumor immunity. Because granzyme B- and perforin-expressing Tr1 cells could specifically eliminate antigen-presenting cells of myeloid origin, we examined whether Tr1 cells in melanoma could eliminate tumor-promoting macrophages and how the interaction between Tr1 cells and macrophages could affect the growth of melanoma cells. Tr1 cells were characterized by high interleukin 10 secretion and low Foxp3 expression and were enriched in the CD4CD49bLAG-3 T-cell fraction. Macrophages derived from peripheral blood monocytes in the presence of modified melanoma-conditioned media demonstrated tumor-promoting capacity, exemplified by improving the proliferation of cocultured A375 malignant melanoma cells. But when primary Tr1 cells were present in the macrophage-A375 coculture, the growth of A375 cells was abrogated. The conventional CD25 Treg cells, however, were unable to inhibit macrophage-mediated increase in tumor cell growth. Further analyses showed that Tr1 cells did not directly eliminate A375 cells, but mediated the killing of tumor-promoting macrophages through the secretion of granzyme B and perforin. The tumor-infiltrating interleukin 10Foxp3CD4 T cells expressed very low levels of granzyme B and perforin, possibly suggested the downregulation of Tr1 cytotoxic capacity in melanoma tumors. Together, these data demonstrated an antitumor function of Tr1 cells through the elimination of tumor-promoting macrophages, which was not shared by conventional Tregs.
在恶性黑色素瘤中，肿瘤相关巨噬细胞在促进肿瘤生长方面发挥多种作用，如在紫外线照射下诱导黑素细胞转化、增加黑色素瘤中的血管生成以及抑制抗肿瘤免疫。由于表达颗粒酶B和穿孔素的Tr1细胞能够特异性清除髓系来源的抗原呈递细胞，我们研究了黑色素瘤中的Tr1细胞是否能够清除促进肿瘤生长的巨噬细胞，以及Tr1细胞与巨噬细胞之间的相互作用如何影响黑色素瘤细胞的生长。Tr1细胞的特征是白细胞介素10分泌高且叉头框蛋白3表达低，并富集于CD4CD49bLAG-3 T细胞亚群中。在改良的黑色素瘤条件培养基存在下，由外周血单核细胞衍生的巨噬细胞表现出促进肿瘤生长的能力，以促进共培养的A375恶性黑色素瘤细胞增殖为例。但是，当原代Tr1细胞存在于巨噬细胞-A375共培养体系中时，A375细胞的生长被抑制。然而，传统的CD25调节性T细胞无法抑制巨噬细胞介导的肿瘤细胞生长增加。进一步分析表明，Tr1细胞不会直接清除A375细胞，而是通过分泌颗粒酶B和穿孔素介导对促进肿瘤生长的巨噬细胞的杀伤。肿瘤浸润的白细胞介素10Foxp3CD4 T细胞表达的颗粒酶B和穿孔素水平非常低，这可能表明黑色素瘤肿瘤中Tr1细胞的细胞毒性能力下调。总之，这些数据证明了Tr1细胞通过清除促进肿瘤生长的巨噬细胞发挥抗肿瘤功能，而传统调节性T细胞不具备这一功能。
