University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI, United States.
Oncoimmunology. 2021 Apr 21;10(1):1912892. doi: 10.1080/2162402X.2021.1912892.
Concurrent blockade of different checkpoint receptors, notably PD-1 and CTLA-4, elicits greater anti-tumor activity for some tumor types, and the combination of different checkpoint receptor inhibitors is an active area of clinical research. We have previously demonstrated that anti-tumor vaccination, by activating CD8 + T cells, increases the expression of PD-1, CTLA-4, LAG-3 and other inhibitory receptors, and the anti-tumor efficacy of vaccination can be increased with checkpoint blockade. In the current study, we sought to determine whether anti-tumor vaccination might be further improved with combined checkpoint blockade. Using an OVA-expressing mouse tumor model, we found that CD8 + T cells activated in the presence of professional antigen presenting cells (APC) expressed multiple checkpoint receptors; however, T cells activated without APCs expressed LAG-3 alone, suggesting that LAG-3 might be a preferred target in combination with vaccination. Using three different murine tumor models, and peptide or DNA vaccines targeting three tumor antigens, we assessed the effects of vaccines with blockade of PD-1 and/or LAG-3 on tumor growth. We report that, in each model, the anti-tumor efficacy of vaccination was increased with PD-1 and/or LAG-3 blockade. However, combined PD-1 and LAG-3 blockade elicited the greatest anti-tumor effect when combined with vaccination in a MycCaP prostate cancer model in which PD-1 blockade alone with vaccination targeting a "self" tumor antigen had less efficacy. These results suggest anti-tumor vaccination might best be combined with concurrent blockade of both PD-1 and LAG-3, and potentially other checkpoint receptors whose expression is increased on CD8 + T cells following vaccine-mediated activation.
同时阻断不同的检查点受体，特别是 PD-1 和 CTLA-4，可引发一些肿瘤类型更强的抗肿瘤活性，并且不同的检查点受体抑制剂的联合是临床研究的活跃领域。我们之前已经证明，通过激活 CD8+T 细胞的抗肿瘤疫苗接种增加了 PD-1、CTLA-4、LAG-3 和其他抑制性受体的表达，并且疫苗接种的抗肿瘤功效可以通过检查点阻断来提高。在当前的研究中，我们试图确定抗肿瘤疫苗接种是否可以通过联合检查点阻断进一步得到改善。使用表达 OVA 的小鼠肿瘤模型，我们发现存在于专业抗原呈递细胞（APC）存在下的 CD8+T 细胞表达多种检查点受体；然而，在没有 APC 的情况下激活的 T 细胞仅表达 LAG-3，这表明 LAG-3 可能是与疫苗接种联合的首选靶标。使用三种不同的小鼠肿瘤模型和针对三种肿瘤抗原的肽或 DNA 疫苗，我们评估了针对 PD-1 和/或 LAG-3 阻断的疫苗对肿瘤生长的影响。我们报告称，在每种模型中，疫苗接种的抗肿瘤功效随着 PD-1 和/或 LAG-3 阻断而增加。然而，在针对“自身”肿瘤抗原的疫苗接种与 PD-1 阻断联合的 MycCaP 前列腺癌模型中，PD-1 和 LAG-3 联合阻断的抗肿瘤效果最大，而针对“自身”肿瘤抗原的疫苗接种与 PD-1 阻断联合的效果较差。这些结果表明，抗肿瘤疫苗接种可能最好与同时阻断 PD-1 和 LAG-3 联合，并且可能与 CD8+T 细胞在疫苗介导的激活后表达增加的其他检查点受体联合。
