Characterization of tumour-infiltrating lymphocytes in a tumour rejection cynomolgus macaque model
Characterization of tumour-infiltrating lymphocytes in a tumour rejection cynomolgus macaque model
复制标题
肿瘤排斥食蟹猴模型中肿瘤浸润淋巴细胞的表征
DOI：
10.1038/s41598-020-65488-x
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发表时间：
2020
影响因子：
4.6
通讯作者：
Hirata Takako
中科院分区：
文献类型：
--
作者：
Satooka Hiroki;Ishigaki Hirohito;Todo Kagefumi;Terada Koji;Agata Yasutoshi;Itoh Yasushi;Ogasawara Kazumasa;Hirata Takako
免疫疗法已成为一种有希望且有效的癌症治疗方法，但临床疗效仍不确定，部分原因是肿瘤微环境中免疫效应细胞的积累不足。更好地了解来自非人灵长类动物肿瘤的肿瘤浸润淋巴细胞（til）可以为在免疫治疗期间改善肿瘤组织中的效应细胞积累提供见解。在这里，我们在食蟹猕猴肿瘤模型中表征了TILs，其中肿瘤被CD4+和CD8+T细胞浸润并最终被排斥。大多数CD4+和CD8+TILs表现出CD45RA - CCR7 -效应记忆表型，但与循环T细胞不同，它们表达CD69，这是组织驻留记忆T （TRM）细胞的标记物。表达cd69的CD8+TILs表达高水平的细胞毒性分子颗粒酶B和共抑制受体PD-1。与TRMcell表型一致，CD8+TILs表达CX3CR1的水平较低，但表达CXCR3的水平高于循环CD8+T细胞。同时，CXCR3的趋化因子配体CXCL9、CXCL10和CXCL11在肿瘤中高水平表达，从而吸引CXCR3+CD8+T细胞。这些结果表明，肿瘤移植的猕猴可以作为研究和优化肿瘤中T细胞积累的有用临床前模型，用于开发新的免疫疗法。
Immunotherapy has emerged as a promising and effective treatment for cancer, yet the clinical benefit is still variable, in part due to insufficient accumulation of immune effector cells in the tumour microenvironment. Better understanding of tumour-infiltrating lymphocytes (TILs) from nonhuman primate tumours could provide insights into improving effector cell accumulation in tumour tissues during immunotherapy. Here, we characterize TILs in a cynomolgus macaque tumour model in which the tumours were infiltrated with CD4+and CD8+T cells and were eventually rejected. The majority of CD4+and CD8+TILs exhibited a CD45RA−CCR7−effector memory phenotype, but unlike circulating T cells, they expressed CD69, a marker for tissue-resident memory T (TRM) cells. CD69-expressing CD8+TILs expressed high levels of the cytotoxic molecule granzyme B and the co-inhibitory receptor PD-1. Consistent with the TRMcell phenotype, CD8+TILs minimally expressed CX3CR1 but expressed CXCR3 at higher levels than circulating CD8+T cells. Meanwhile, CXCL9, CXCL10 and CXCL11, chemokine ligands for CXCR3, were expressed at high levels in the tumours, thus attracting CXCR3+CD8+T cells. These results indicate that tumour-transplanted macaques can be a useful preclinical model for studying and optimizing T cell accumulation in tumours for the development of new immunotherapies.