Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production.
Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production.
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CTLA-4 阻断和 4-1BB 激活相结合，通过增加 T 细胞浸润、增殖和细胞因子产生来增强肿瘤排斥。
DOI：
10.1371/journal.pone.0019499
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发表时间：
2011-04-29
期刊：
影响因子：
3.7
通讯作者：
Allison JP
中科院分区：
文献类型：
--
作者：
Curran MA;Kim M;Montalvo W;Al-Shamkhani A;Allison JP
共抑制受体细胞毒性T淋巴细胞抗原4(CTLA-4)减弱免疫反应，防止自身免疫，然而，肿瘤利用这一途径来逃避宿主T细胞反应。T细胞共刺激受体4-1BB在激活后在T细胞上瞬时上调，并在激活时促进其增殖和炎性细胞因子的产生。阻断CTLA-4或激活4-1BB的抗体可促进某些小鼠肿瘤的排斥反应，但不能作为单一药物治愈免疫原性差的肿瘤，如B16黑色素瘤。我们发现，在α配体而不是GM-CSF型黑色素瘤疫苗的背景下，结合αCTLA-4和Flt3-1BB抗体，促进了肿瘤排斥反应的协同水平。4-1BB的激活可诱导CD8+T细胞向肿瘤细胞的强烈渗透，并促进CD8+T细胞的增殖，而CTLA-4阻断对CD4+效应T细胞也有同样的作用。抗4-1BB抗体也能抑制调节性T细胞对肿瘤的侵袭。4-1BB的激活强烈刺激疫苗和肿瘤引流淋巴结以及肿瘤本身产生炎性细胞因子。CTLA-4阻断剂的加入进一步增加了疫苗引流结节和肿瘤中CD_4+效应T细胞产生的干扰素-γ。无论是否阻断CTLA-4，抗4-1BB治疗均可诱导肿瘤中约75%的CD8+和45%的CD4+效应T细胞表达杀伤细胞凝集素样受体G1(KLRG1)。联合抗体治疗的肿瘤显示，这些KLRG1CD4+效应T细胞的浸润率是单独使用α4-1BB治疗的肿瘤的1.7倍。这项研究表明，在合适的疫苗背景下，将T细胞共抑制阻断与αCTLA-4和主动共刺激与α4-1BB相结合，可促进对B16黑色素瘤的排斥反应。此外，我们发现KLRG1是监测该疗法所引起的抗肿瘤免疫反应的有用标记物。这些发现应该有助于设计未来黑色素瘤免疫疗法的试验。
The co-inhibitory receptor Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) attenuates immune responses and prevent autoimmunity, however, tumors exploit this pathway to evade the host T-cell response. The T-cell co-stimulatory receptor 4-1BB is transiently upregulated on T-cells following activation and increases their proliferation and inflammatory cytokine production when engaged. Antibodies which block CTLA-4 or which activate 4-1BB can promote the rejection of some murine tumors, but fail to cure poorly immunogenic tumors like B16 melanoma as single agents. We find that combining αCTLA-4 and α4-1BB antibodies in the context of a Flt3-ligand, but not a GM-CSF, based B16 melanoma vaccine promoted synergistic levels of tumor rejection. 4-1BB activation elicited strong infiltration of CD8+ T-cells into the tumor and drove the proliferation of these cells, while CTLA-4 blockade did the same for CD4+ effector T-cells. Anti-4-1BB also depressed regulatory T-cell infiltration of tumors. 4-1BB activation strongly stimulated inflammatory cytokine production in the vaccine and tumor draining lymph nodes and in the tumor itself. The addition of CTLA-4 blockade further increased IFN-γ production from CD4+ effector T-cells in the vaccine draining node and the tumor. Anti 4-1BB treatment, with or without CTLA-4 blockade, induced approximately 75% of CD8+ and 45% of CD4+ effector T-cells in the tumor to express the killer cell lectin-like receptor G1 (KLRG1). Tumors treated with combination antibody therapy showed 1.7-fold greater infiltration by these KLRG1+CD4+ effector T-cells than did those treated with α4-1BB alone. This study shows that combining T-cell co-inhibitory blockade with αCTLA-4 and active co-stimulation with α4-1BB promotes rejection of B16 melanoma in the context of a suitable vaccine. In addition, we identify KLRG1 as a useful marker for monitoring the anti-tumor immune response elicited by this therapy. These findings should aid in the design of future trials for the immunotherapy of melanoma.
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影响因子：
8.6
作者：
Li, Betty;Lin, Jianmin;Jooss, Karin
通讯作者：
Jooss, Karin
影响因子：
15.3
作者：
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作者：
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