Persistent antigen at vaccination sites induces tumor-specific CD8⁺ T cell sequestration, dysfunction and deletion.
Persistent antigen at vaccination sites induces tumor-specific CD8⁺ T cell sequestration, dysfunction and deletion.
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作者：
为了理解为什么癌症疫苗诱导的T细胞通常不能根除肿瘤，我们研究了在不完全弗氏佐剂（IFA）中接种gp 100黑色素瘤肽的小鼠的免疫应答，该佐剂通常用于临床癌症疫苗试验。肽/IFA疫苗接种引发了肿瘤特异性CD 8 + T细胞，其不在肿瘤中积累，而是在持续的、富含抗原的疫苗接种部位积累。一旦到达那里，致敏的T细胞变得功能失调，并经历抗原驱动的干扰素-γ（IFN-γ）和Fas配体（FasL）介导的凋亡，导致对后续疫苗接种的低反应性。提供抗CD 40抗体、Toll样受体7（TLR 7）激动剂和白细胞介素-2（IL-2）可减少T细胞凋亡，但不能防止疫苗接种部位隔离。非持久性疫苗制剂将T细胞定位向肿瘤转移，诱导上级抗肿瘤活性，同时减少全身性T细胞功能障碍并促进记忆形成。持续存在的肽/IFA疫苗库可以在疫苗接种部位诱导特异性T细胞隔离、功能障碍和缺失;短寿命制剂可以克服这些限制并导致基于肽的癌症疫苗的更大治疗功效。
To understand why cancer vaccine-induced T cells often fail to eradicate tumors, we studied immune responses in mice vaccinated with gp100 melanoma peptide in incomplete Freund’s adjuvant (IFA), commonly used in clinical cancer vaccine trials. Peptide/IFA vaccination primed tumor-specific CD8+ T cells, which accumulated not in tumors but at the persisting, antigen-rich vaccination site. Once there, primed T cells became dysfunctional and underwent antigen-driven, Interferon-γ (IFN-γ) and Fas ligand (FasL)-mediated apoptosis, resulting in hyporesponsiveness to subsequent vaccination. Provision of anti-CD40 antibody, Toll-like receptor 7 (TLR7) agonist and interleukin-2 (IL-2) reduced T cell apoptosis but did not prevent vaccination site sequestration. A non-persisting vaccine formulation shifted T cell localization towards tumors, inducing superior anti-tumor activity while reducing systemic T cell dysfunction and promoting memory formation. Persisting peptide/IFA vaccine depots can induce specific T cell sequestration, dysfunction and deletion at vaccination sites; short-lived formulations may overcome these limitations and result in greater therapeutic efficacy of peptide-based cancer vaccines.
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影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.
DOI：
10.1158/1055-9965.epi-10-0565
发表时间：
2010-10
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Ma W;Wang M;Wang ZQ;Sun L;Graber D;Matthews J;Champlin R;Yi Q;Orlowski RZ;Kwak LW;Weber DM;Thomas SK;Shah J;Kornblau S;Davis RE
通讯作者：
Davis RE
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
11.2
作者：
Ly, Long V.;Sluijter, Marjolein;van Hall, Thorbald
通讯作者：
van Hall, Thorbald
影响因子：
4.4
作者：
Bijker, Martijn S.;van den Eeden, Susan J. F.;van der Burg, Sjoerd H.
通讯作者：
van der Burg, Sjoerd H.