Engagement of programmed death 1 receptor (PD-1) and its ligand PD-L1/2 induces a signal transduction pathway that inhibits the activity of tumor-infiltrating cytotoxic T lymphocytes and promotes tumor growth and metastasis. Antibodies blocking PD-1 or PD-L1 can restore antitumor T cell responses and cause long-term remission in a subset of cancer patients with advanced or refractory tumors. In this study, we asked whether PD-L1 vaccination could confer tumor control in mouse tumor models. To address the central tolerance toward self-molecules, we fused the extracellular domain of PD-L1 (PD-L1E) to the C-terminal of the translocation domain of diphtheria toxin (DTT). DTT is able to elicit CD4+ T cell responses required for inducing robust immune responses against self-molecules. The fusion molecule is called DPDL1E. When formulated with incomplete Freund’s adjuvant (IFA), DPDL1E elicited robust immune responses biased toward the Th1 type and inhibited tumor growth in both preventive and therapeutic mouse tumor models. We further showed that the anti-DPDL1E sera blocked PD-L1 binding to PD-1 in vitro. The DPDL1E vaccination increased the levels of tumor-infiltrating T lymphocytes (TILs) and reduced the levels of myeloid-derived suppressor cells (MDSCs) as well as exhausted LAG3+PD-1+ CD8+ T cells. All of these data suggest that DPDL1E vaccination reverses the suppressive phenotype of the tumor microenvironment and that it is a promising strategy for cancer therapy.

参与程序性死亡1受体（PD-1）及其配体PD-L1 / 2会诱导信号转导途径，抑制肿瘤浸润的细胞毒性T淋巴细胞的活性并促进肿瘤的生长和转移。阻断PD-1或PD-L1的抗体可以在部分患有晚期或难治性肿瘤的癌症患者中恢复抗肿瘤T细胞反应并引起长期缓解。在这项研究中，我们问PD-L1疫苗是否可以在小鼠肿瘤模型中赋予肿瘤控制能力。为了解决对自身分子的中心耐受性，我们将PD-L1的胞外域（PD-L1E）融合到白喉毒素（DTT）易位域的C末端。DTT能够引发诱导针对自身分子的强大免疫反应所需的CD4 + T细胞反应。融合分子称为DPDL1E。当用不完全弗氏佐剂（IFA）配制时，在预防性和治疗性小鼠肿瘤模型中，DPDL1E会引发偏向Th1型的强大免疫反应，并抑制肿瘤的生长。我们进一步表明抗DPDL1E血清阻断了PD-L1与PD-1的结合体外。DPDL1E疫苗接种可增加肿瘤浸润性T淋巴细胞（TIL）的水平，并减少髓样来源的抑制细胞（MDSCs）以及疲惫的LAG3 + PD-1 + CD8 + T细胞的水平。所有这些数据表明，DPDL1E疫苗接种可逆转肿瘤微环境的抑制表型，这是一种有前途的癌症治疗策略。