Dendritic cells in antitumor immune responses .1. Defective antigen presentation in tumor-bearing hosts
Dendritic cells in antitumor immune responses .1. Defective antigen presentation in tumor-bearing hosts
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DOI：
10.1006/cimm.1996.0139
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发表时间：
1996-05-25
影响因子：
4.3
通讯作者：
Carbone, DP
中科院分区：
文献类型：
--
作者：
Gabrilovich, DI;Ciernik, IF;Carbone, DP
我们在转染了人类p53基因突变体的BALB/c小鼠中研究了诱导特异性抗肿瘤细胞毒性T细胞反应，我们观察到小鼠在用最小致死剂量的肿瘤细胞攻击后5天就对肽特异性CTL的诱导产生了抗性，并进一步表征了产生这种效应的细胞类型。在肽脉冲树突状细胞（DC）免疫后，研究了CD4（+）和CD8(+) T细胞在这种反应中的作用。在体外肽再刺激过程中，CD4（+）细胞的耗竭降低了对照小鼠的特异性裂解水平，而CD8(+) T细胞的耗竭则完全消除了这种裂解。在重新刺激免疫荷瘤小鼠的细胞时，替换来自免疫对照小鼠的CD8（+）细胞不会改变特异性裂解的水平，用来自对照小鼠的CD4（+）细胞替换来自荷瘤小鼠的CD4（+）细胞可以改善CTL反应，尽管这种反应没有达到控制值。从荷瘤小鼠中分离的肽脉冲树突状细胞在对照动物中诱导特异性CTL的能力显著降低，在体外对对照小鼠免疫T细胞的再刺激能力也显著降低。来自荷瘤小鼠的DC也降低了刺激对照异体T细胞的能力。用来自对照动物的DC再刺激免疫荷瘤小鼠的T细胞，而不是来自荷瘤小鼠的DC，显著增加了对对照水平的特异性CTL反应。相同浓度的巨噬细胞不能改善CTL功能，因此，DC抗原呈递缺陷似乎是荷瘤小鼠CTL对肽抗原无反应的主要决定因素，添加对照DC可以恢复特异性裂解。这些数据为以肽为基础的癌症免疫治疗的新方法提供了基础。(C) 1996学术出版社，Inc.
Induction of specific antitumor cytotoxic T cell responses was studied in BALB/c mice bearing tumors transfected with a mutant human p53 minigene, We observed that mice were resistant to the induction of peptide-specific CTL as early as 5 days after challenge with a minimal lethal dose of tumor cells, and the cell types responsible for this effect were further characterized. The contribution of CD4(+) and CD8(+) T cells in this response was studied after peptide-pulsed dendritic cell (DC) immunization. In vitro depletion of CD4(+) cells during peptide restimulation reduced the level of specific lysis in control mice, and depletion of CD8(+) T cells completely abrogated it. Substitution of CD8(+) cells from immunized control mice during restimulation of cells from immunized tumor-bearing mice did not change the level of specific lysis, Substitution of the CD4(+) from tumor-bearing mice by CD4(+) cells from control mice improved CTL response, although this response did not reach control values. Peptide-pulsed dendritic cells isolated from tumor-bearing mice showed a significantly reduced ability to induce specific CTL in control animals and reduced ability to restimulate immune T cells from control mice in vitro. DC from tumor-bearing mice also had a reduced ability to stimulate control allogeneic T cells. Restimulation of T cells from immunized tumor-bearing mice with DC from control animals, but not from tumor-bearing mice, dramatically increased specific CTL responses to control levels. Macrophages at the same concentration were not able to improve CTL function, Thus, defective antigen presentation by DC appears to be a major determinant for CTL nonresponsiveness to peptide antigens in tumor-bearing mice, and addition of control DC can restore specific lysis. These data provide a basis for new approaches to peptide-based cancer immunotherapy. (C) 1996 Academic Press, Inc.