Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, BC V8R 6V5, Canada.
Breast Cancer Res Treat. 2010 Jun;121(3):753-63. doi: 10.1007/s10549-009-0559-y. Epub 2009 Sep 30.
Adoptive immunotherapy shows promise for the treatment of cancer; however, partial or mixed responses remain common outcomes due to the heterogeneity of tumours. We studied three murine mammary tumour lines that express an ovalbumin-tagged version of HER-2/neu and reproducibly undergo complete regression (CR), partial regression (PR), or progressive disease (PD) after adoptive transfer of ovalbumin-specific CD8(+) (OT-I) and CD4(+) (OT-II) T cells. The three tumour lines were implanted in immunocompetent C57Bl/6 host mice, and established tumours were treated by adoptive transfer of naive OT-I and OT-II T cells. Tumours of the CR and PR classes triggered almost indistinguishable T cell responses in terms of activation, proliferation, trafficking to the tumour site, infiltration of tumour stroma, and intratumoural T cell proliferation; however, tumours of the PR class showed reduced infiltration of tumour epithelium by donor T cells. PD responses were associated with early impairment of T cell activation and proliferation in draining lymph node, followed by negligible infiltration of tumour tissue by donor T cells. Histopathological determinants of outcome were investigated through an unsupervised analysis of 64 untreated tumours representing the three response classes. Tumours of the CR class had proportionately more stroma, which had a looser, more collagen-rich histological appearance. Thus, the amount and composition of tumour stroma distinguished successfully (CR) from unsuccessful (PR or PD) outcomes after adoptive T cell transfer, a finding that might facilitate the design of immunotherapy trials for human breast cancer.
过继免疫疗法在癌症治疗方面显示出了一定的前景，但由于肿瘤的异质性，部分或混合反应仍然是常见的结果。我们研究了三种表达 HER-2/neu 标记物的鼠乳腺肿瘤细胞系，这些细胞系在过继转移卵清蛋白特异性 CD8(+) (OT-I) 和 CD4(+) (OT-II) T 细胞后，可重复地经历完全消退 (CR)、部分消退 (PR) 或进行性疾病 (PD)。这三种肿瘤细胞系被植入免疫功能正常的 C57Bl/6 宿主小鼠体内，用未成熟的 OT-I 和 OT-II T 细胞过继转移来治疗已建立的肿瘤。CR 和 PR 类肿瘤在 T 细胞激活、增殖、向肿瘤部位迁移、浸润肿瘤基质和肿瘤内 T 细胞增殖方面引发了几乎无法区分的 T 细胞反应；然而，PR 类肿瘤中供体 T 细胞对肿瘤上皮的浸润减少。PD 反应与引流淋巴结中 T 细胞激活和增殖的早期受损有关，随后供体 T 细胞对肿瘤组织的浸润可忽略不计。通过对代表三种反应类型的 64 个未经治疗的肿瘤进行无监督分析，研究了结局的组织病理学决定因素。CR 类肿瘤的基质比例更高，其组织学外观更疏松，富含胶原。因此，肿瘤基质的数量和组成成功地区分了过继 T 细胞转移后的成功（CR）和不成功（PR 或 PD）结果，这一发现可能有助于设计人类乳腺癌的免疫治疗试验。
