Swim Across America Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
J Exp Med. 2012 Oct 22;209(11):2113-26. doi: 10.1084/jem.20120532. Epub 2012 Sep 24.
Harnessing the adaptive immune response to treat malignancy is now a clinical reality. Several strategies are used to treat melanoma; however, very few result in a complete response. CD4(+) T cells are important and potent mediators of anti-tumor immunity and adoptive transfer of specific CD4(+) T cells can promote tumor regression in mice and patients. OX40, a costimulatory molecule expressed primarily on activated CD4(+) T cells, promotes and enhances anti-tumor immunity with limited success on large tumors in mice. We show that OX40 engagement, in the context of chemotherapy-induced lymphopenia, induces a novel CD4(+) T cell population characterized by the expression of the master regulator eomesodermin that leads to both terminal differentiation and central memory phenotype, with concomitant secretion of Th1 and Th2 cytokines. This subpopulation of CD4(+) T cells eradicates very advanced melanomas in mice, and an analogous population of human tumor-specific CD4(+) T cells can kill melanoma in an in vitro system. The potency of the therapy extends to support a bystander killing effect of antigen loss variants. Our results show that these uniquely programmed effector CD4(+) T cells have a distinctive phenotype with increased tumoricidal capability and support the use of immune modulation in reprogramming the phenotype of CD4(+) T cells.
利用适应性免疫反应来治疗恶性肿瘤现在已成为临床现实。有几种策略可用于治疗黑色素瘤；然而，只有极少数能产生完全反应。CD4(+)T 细胞是抗肿瘤免疫的重要和有效介质，特异性 CD4(+)T 细胞的过继转移可促进小鼠和患者的肿瘤消退。OX40，一种主要在激活的 CD4(+)T 细胞上表达的共刺激分子，在小鼠的大肿瘤中，通过有限的成功促进和增强了抗肿瘤免疫。我们表明，在化疗诱导的淋巴细胞减少的情况下，OX40 的结合诱导了一种新型的 CD4(+)T 细胞群体，其特征是表达主调控因子 eomesodermin，导致终末分化和中央记忆表型，同时分泌 Th1 和 Th2 细胞因子。这种 CD4(+)T 细胞亚群可根除小鼠的晚期黑色素瘤，并且人类肿瘤特异性 CD4(+)T 细胞的类似群体可在体外系统中杀死黑色素瘤。该疗法的效力扩展到支持抗原缺失变体的旁观者杀伤效应。我们的结果表明，这些经过独特编程的效应 CD4(+)T 细胞具有独特的表型，具有增强的杀肿瘤能力，并支持在重新编程 CD4(+)T 细胞表型中使用免疫调节。
