Division of Basic Research, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA.
Clin Cancer Res. 2011 Oct 1;17(19):6174-84. doi: 10.1158/1078-0432.CCR-11-1111. Epub 2011 Aug 19.
Cancer-initiating cells (CIC) are considered to represent the subpopulation of tumor cells that is resistant to conventional cancer treatments, highly tumorigenic in immunodeficient mice, and responsible for tumor recurrence and metastasis. Based on an elevated aldehyde dehydrogenase (ALDH) activity attributable to ALDH1/3 isoforms, ALDH(bright) cells have been identified and isolated from tumors and shown to have characteristics of CIC. The ALDH1A1 isoform was previously identified as a tumor antigen recognized by CD8(+) T cells. This study examines the ability of ALDH1A1-specific CD8(+) T cells to eliminate ALDH(bright) cells and control tumor growth and metastases.
ALDH(bright) cells were isolated by flow cytometry using ALDEFLUOR from HLA-A2(+) human head and neck, breast, and pancreas carcinoma cell lines and tested for their tumorigenicity in immunodeficient mice. ALDH1A1-specific CD8(+) T cells were generated in vitro and tested for their ability to eliminate CICs in vitro and in vivo by adoptive transfer to immunodeficient mice bearing human tumor xenografts.
ALDH(bright) cells isolated by flow cytometry from HLA-A2(+) breast, head and neck, and pancreas carcinoma cell lines at low numbers (500 cells) were tumorigenic in immunodeficient mice. ALDH(bright) cells present in these cell lines, xenografts, or surgically removed lesions were recognized by ALDH1A1-specific CD8(+) T cells in vitro. Adoptive therapy with ALDH1A1-specific CD8(+) T cells eliminated ALDH(bright) cells, inhibited tumor growth and metastases, or prolonged survival of xenograft-bearing immunodeficient mice.
The results of this translational study strongly support the potential of ALDH1A1-based immunotherapy to selectively target CICs in human cancer.
癌症起始细胞（CIC）被认为代表了对常规癌症治疗具有抗性、在免疫缺陷小鼠中高度致瘤、并导致肿瘤复发和转移的肿瘤细胞亚群。基于归因于 ALDH1/3 同工酶的升高的醛脱氢酶（ALDH）活性，已经从肿瘤中鉴定和分离出 ALDH（bright）细胞，并显示出 CIC 的特征。ALDH1A1 同工型先前被鉴定为 CD8(+) T 细胞识别的肿瘤抗原。本研究检查了 ALDH1A1 特异性 CD8(+) T 细胞消除 ALDH（bright）细胞并控制肿瘤生长和转移的能力。
使用 ALDEFLUOR 通过流式细胞术从 HLA-A2(+)人头颈部、乳腺和胰腺癌细胞系中分离 ALDH（bright）细胞，并在免疫缺陷小鼠中测试其致瘤性。体外生成 ALDH1A1 特异性 CD8(+) T 细胞，并通过过继转移到携带人肿瘤异种移植物的免疫缺陷小鼠中，测试其在体外和体内消除 CIC 的能力。
从 HLA-A2(+)乳腺、头颈部和胰腺癌细胞系中以低数量（500 个细胞）通过流式细胞术分离的 ALDH（bright）细胞在免疫缺陷小鼠中具有致瘤性。这些细胞系、异种移植物或手术切除的病变中存在的 ALDH（bright）细胞可被 ALDH1A1 特异性 CD8(+) T 细胞在体外识别。过继转移 ALDH1A1 特异性 CD8(+) T 细胞消除了 ALDH（bright）细胞，抑制了肿瘤生长和转移，或延长了携带异种移植物的免疫缺陷小鼠的存活时间。
这项转化研究的结果强烈支持基于 ALDH1A1 的免疫疗法选择性靶向人类癌症中的 CIC 的潜力。
