Authors' Affiliations: Department of Obstetrics and Gynecology, Ovarian Cancer Research Center; and Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Clin Cancer Res. 2014 Jan 1;20(1):44-55. doi: 10.1158/1078-0432.CCR-13-0945. Epub 2013 Sep 17.
Upregulation of CD137 (4-1BB) on recently activated CD8(+) T cells has been used to identify rare viral or tumor antigen-specific T cells from peripheral blood. Here, we evaluated the immunobiology of CD137 in human cancer and the utility of a CD137-positive separation methodology for the identification and enrichment of fresh tumor-reactive tumor-infiltrating lymphocytes (TIL) or tumor-associated lymphocytes (TAL) from ascites for use in adoptive immunotherapy.
TILs from resected ovarian cancer or melanoma were measured for surface CD137 expression directly or after overnight incubation in the presence of tumor cells and homeostatic cytokines. CD137(pos) TILs were sorted and evaluated for antitumor activity in vitro and in vivo.
Fresh ovarian TILs and TALs naturally expressed higher levels of CD137 than circulating T cells. An HLA-dependent increase in CD137 expression was observed following incubation of fresh enzyme-digested tumor or ascites in IL-7 and IL-15 cytokines, but not IL-2. Enriched CD137(pos) TILs, but not PD-1(pos) or PD-1(neg) CD137(neg) cells, possessed autologous tumor reactivity in vitro and in vivo. In melanoma studies, all MART-1-specific CD8(+) TILs upregulated CD137 expression after incubation with HLA-matched, MART-expressing cancer cells and antigen-specific effector function was restricted to the CD137(pos) subset in vitro. CD137(pos) TILs also mediated superior antitumor effects in vivo, compared with CD137(neg) TILs.
Our findings reveal a role for the TNFR-family member CD137 in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of TILs, thus rationalizing its agonistic engagement in vivo and its use in TIL selection for adoptive immunotherapy trials.
CD137（4-1BB）在新近激活的 CD8（+）T 细胞上的上调已被用于从外周血中鉴定罕见的病毒或肿瘤抗原特异性 T 细胞。在这里，我们评估了 CD137 在人类癌症中的免疫生物学，以及 CD137 阳性分离方法在鉴定和富集来自腹水的新鲜肿瘤反应性肿瘤浸润淋巴细胞（TIL）或肿瘤相关淋巴细胞（TAL）用于过继免疫治疗中的应用。
从切除的卵巢癌或黑色素瘤中分离 TIL，直接或在存在肿瘤细胞和稳态细胞因子的情况下过夜孵育后测量表面 CD137 表达。对 CD137（pos）TIL 进行分选，并在体外和体内评估其抗肿瘤活性。
新鲜卵巢 TIL 和 TAL 自然表达的 CD137 水平高于循环 T 细胞。在 IL-7 和 IL-15 细胞因子中孵育新鲜酶消化的肿瘤或腹水后，观察到 HLA 依赖性 CD137 表达增加，但在 IL-2 中没有。与 PD-1（pos）或 PD-1（neg）CD137（neg）细胞相比，仅富集的 CD137（pos）TIL 具有体外和体内的自体肿瘤反应性。在黑色素瘤研究中，所有 MART-1 特异性 CD8（+）TIL 在与 HLA 匹配的表达 MART 的癌细胞孵育后均上调 CD137 表达，并且抗原特异性效应功能仅限于体外的 CD137（pos）亚群。与 CD137（neg）TIL 相比，CD137（pos）TIL 还在体内介导了更好的抗肿瘤作用。
我们的研究结果揭示了 TNFR 家族成员 CD137 在人类癌症免疫生物学中的作用，它在肿瘤反应性 TIL 亚群中优先表达，从而使其在体内激动性结合具有合理性，并使其在用于过继免疫治疗试验的 TIL 选择中得到应用。
