Grover Amelia, Kim Grace J, Lizée Gregory, Tschoi Mary, Wang Gang, Wunderlich John R, Rosenberg Steven A, Hwang Sam T, Hwu Patrick
Surgery Branch and Dermatology Branch, National Cancer Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA.
Clin Cancer Res. 2006 Oct 1;12(19):5801-8. doi: 10.1158/1078-0432.CCR-05-2421.
The identification of tumor antigens recognized by cytotoxic and T helper lymphocytes has led to the development of specific cancer vaccines. Immunization with tumor antigen-pulsed dendritic cells has proved effective at eliciting elevated levels of tumor antigen-specific T cells in patient blood, but objective clinical responses remain rare, suggesting that vaccine-induced T cells are not trafficking optimally to site(s) of tumor burden. Accumulating evidence from animal models suggests that route of immunization can have a substantial influence on the subsequent migration of primed, activated T cells in vivo.
In a clinical trial designed to elicit more effective cytotoxic T-cell mediated antitumor responses, metastatic melanoma patients were immunized directly via a peripheral intralymphatic route with autologous dendritic cells pulsed with HLA-A*0201-restricted melanoma-associated peptide antigens derived from MART-1 and gp100.
Within 10 days of intralymphatic dendritic cell vaccination, four of six patients developed dramatic and diffuse erythematous rashes in sun-exposed areas of skin that showed extensive T-cell infiltration. CTLs grown from rash biopsies were strongly enriched for tumor antigen-specific T cells that had elevated expression of cutaneous lymphocyte antigen and chemokine receptor-6, consistent with a skin-homing phenotype. Of note, the only patient in the study with cutaneously localized disease showed a significant regression of metastatic lesions following the development of a surrounding rash.
The evidence presented here is consistent with immunization studies in animal models and supports the concept that T cells are "imprinted" in peripheral lymph node sites to express specific ligands and chemokine receptors that allow them to migrate to skin. Furthermore, the preferential migration of the T cells to sun-exposed cutaneous sites suggests that inflammation plays a critical role in this migration. These observations suggest that further study of the effects of immunization route and inflammation on T-cell migration in humans is warranted, and could lead to vaccination approaches that would more reliably direct trafficking of activated T cells to diverse sites of metastatic disease.
细胞毒性淋巴细胞和辅助性T淋巴细胞所识别的肿瘤抗原的鉴定推动了特异性癌症疫苗的研发。用肿瘤抗原脉冲树突状细胞进行免疫已被证明能有效诱导患者血液中肿瘤抗原特异性T细胞水平升高，但客观临床反应仍然罕见，这表明疫苗诱导的T细胞未能最佳地迁移至肿瘤负荷部位。来自动物模型的越来越多的证据表明，免疫途径可对体内致敏的活化T细胞随后的迁移产生重大影响。
在一项旨在引发更有效的细胞毒性T细胞介导的抗肿瘤反应的临床试验中，转移性黑色素瘤患者通过外周淋巴管内途径直接用脉冲了源自MART-1和gp100的HLA-A*0201限制性黑色素瘤相关肽抗原的自体树突状细胞进行免疫。
在淋巴管内树突状细胞疫苗接种后的10天内，6名患者中有4名在皮肤暴露于阳光的区域出现了剧烈且弥漫性的红斑皮疹，这些皮疹显示出广泛的T细胞浸润。从皮疹活检组织中培养出的细胞毒性T淋巴细胞中富含肿瘤抗原特异性T细胞，这些T细胞的皮肤淋巴细胞抗原和趋化因子受体-6表达升高，与皮肤归巢表型一致。值得注意的是，该研究中唯一患有皮肤局限性疾病的患者在出现周围皮疹后，转移病灶出现了显著消退。
此处提供的证据与动物模型中的免疫研究一致，并支持这样的概念，即T细胞在周围淋巴结部位“印记”表达特定配体和趋化因子受体，使其能够迁移至皮肤。此外，T细胞优先迁移至暴露于阳光的皮肤部位表明炎症在这种迁移中起关键作用。这些观察结果表明，有必要进一步研究免疫途径和炎症对人体T细胞迁移的影响，这可能会带来能更可靠地将活化T细胞导向转移性疾病不同部位的疫苗接种方法。
