Yang Sixun, Linette Gerald P, Longerich Simonne, Haluska Frank G
Division of Hematology-Oncology, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
J Immunol. 2002 Jul 1;169(1):531-9. doi: 10.4049/jimmunol.169.1.531.
Anchor residue-modified peptides derived from tumor-associated Ag have demonstrated success in engendering immune responses in clinical studies. However, tumor regression does not always correlate with immune responses. One hypothesis to explain this is that CTL resulting from such immunization approaches are variable in antitumor potency. In the present study, we evaluated this hypothesis by characterizing the activity of tumor-associated Ag-specific CTL. We chose an anchor residue-modified peptide from gp100, G209-2M, and used peptide-pulsed dendritic cells to generate CTL from PBMC of HLA-A2(+) normal donors. The specificities and avidities of the resulting CTL were evaluated. The results demonstrate that CTL generated by G209-2M can be classified into three categories: G209-2M-specific CTL which are cytotoxic only to G209-2M-pulsed targets; peptide-specific CTL which recognize both G209 and G209-2M peptides but not melanomas; and melanoma-reactive CTL which recognize peptide-pulsed targets as well as HLA-A2(+)gp100(+) melanomas. CTL that kill only peptide-pulsed targets require a higher peptide concentration to mediate target lysis, whereas CTL that lyse melanomas need a lower peptide concentration. Increasing peptide density on melanomas by loading exogenous G209 peptide enhances their sensitivity to peptide-specific CTL. High avidity CTL clones also demonstrate potent antimelanoma activity in melanoma model in nude mice. Injection of G209 peptide around transplanted tumors significantly enhances the antitumor activity of low avidity CTL. These results suggest that peptide stimulation causes expansion of T cell populations with a range of avidities. Successful immunotherapy may require selective expansion of the higher-avidity CTL and intratumor injection of the peptide may enhance the effect of peptide vaccines.
源自肿瘤相关抗原的锚定残基修饰肽在临床研究中已成功引发免疫反应。然而，肿瘤消退并不总是与免疫反应相关。一种解释这一现象的假说是，这种免疫方法产生的细胞毒性T淋巴细胞（CTL）在抗肿瘤效力方面存在差异。在本研究中，我们通过表征肿瘤相关抗原特异性CTL的活性来评估这一假说。我们从gp100中选择了一种锚定残基修饰肽G209-2M，并使用肽脉冲树突状细胞从HLA-A2(+)正常供体的外周血单核细胞（PBMC）中产生CTL。评估了所得CTL的特异性和亲和力。结果表明，由G209-2M产生的CTL可分为三类：仅对G209-2M脉冲靶细胞具有细胞毒性的G209-2M特异性CTL；识别G209和G209-2M肽但不识别黑色素瘤的肽特异性CTL；以及识别肽脉冲靶细胞以及HLA-A2(+)gp100(+)黑色素瘤的黑色素瘤反应性CTL。仅杀伤肽脉冲靶细胞的CTL需要更高的肽浓度来介导靶细胞裂解，而裂解黑色素瘤的CTL需要较低的肽浓度。通过加载外源性G209肽增加黑色素瘤上的肽密度可增强其对肽特异性CTL的敏感性。高亲和力CTL克隆在裸鼠黑色素瘤模型中也表现出强大的抗黑色素瘤活性。在移植肿瘤周围注射G209肽可显著增强低亲和力CTL的抗肿瘤活性。这些结果表明，肽刺激会导致具有一系列亲和力的T细胞群体扩增。成功的免疫治疗可能需要选择性扩增高亲和力CTL，并且肿瘤内注射肽可能会增强肽疫苗的效果。
