Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy.
Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy.
复制标题
DOI：
10.1371/journal.pone.0153053
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pilon-Thomas S
中科院分区：
文献类型：
--
作者：
Kodumudi KN;Siegel J;Weber AM;Scott E;Sarnaik AA;Pilon-Thomas S
肿瘤浸润淋巴细胞（TIL）与癌症患者生存率的提高有关。在肿瘤微环境中，调节细胞和共抑制性免疫检查点分子的表达可导致 TIL 失活。因此，需要制定破坏这些负调节因子的策略，以实现强大的抗肿瘤免疫反应。我们评估了免疫检查点的封锁及其对 T 细胞浸润和功能的影响。我们检查了 TIL 在体外和体内诱导肿瘤特异性免疫反应的能力。从荷瘤小鼠中分离出的 TIL 具有肿瘤特异性，并表达共抑制性免疫检查点分子。施用针对免疫检查点的单克隆抗体导致肿瘤生长显着延迟。然而，与其他组相比，抗 PD-L1 抗体治疗的小鼠 T 细胞浸润和 IFN-γ 产量显着增加。来自抗 PD-L1 抗体治疗小鼠肿瘤的体外扩增 TIL 的过继转移导致肿瘤生长显着延迟。阻断共抑制性免疫检查点可能是改善 TIL 浸润和功能的有效策略。
Tumor-infiltrating lymphocytes (TIL) has been associated with improved survival in cancer patients. Within the tumor microenvironment, regulatory cells and expression of co-inhibitory immune checkpoint molecules can lead to the inactivation of TIL. Hence, there is a need to develop strategies that disrupt these negative regulators to achieve robust anti-tumor immune responses. We evaluated the blockade of immune checkpoints and their effect on T cell infiltration and function. We examined the ability of TIL to induce tumor-specific immune responses in vitro and in vivo. TIL isolated from tumor bearing mice were tumor-specific and expressed co-inhibitory immune checkpoint molecules. Administration of monoclonal antibodies against immune checkpoints led to a significant delay in tumor growth. However, anti-PD-L1 antibody treated mice had a significant increase in T cell infiltration and IFN-γ production compared to other groups. Adoptive transfer of in vitro expanded TIL from tumors of anti-PD-L1 antibody treated mice led to a significant delay in tumor growth. Blockade of co-inhibitory immune checkpoints could be an effective strategy to improve TIL infiltration and function.