Center for Tumor Immunology Research, University of Rochester Medical Center, Rochester, New York, USA.
Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
J Immunother Cancer. 2023 May;11(5). doi: 10.1136/jitc-2023-006842.
Stereotactic body radiotherapy (SBRT) induces immunogenic cell death, leading to subsequent antitumor immune response that is in part counterbalanced by activation of immune evasive processes, for example, upregulation of programmed cell death-ligand 1 (PD-L1) and adenosine generating enzyme, CD73. CD73 is upregulated in pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissue and high expression of CD73 in PDACs is associated with increased tumor size, advanced stage, lymph node involvement, metastasis, PD-L1 expression and poor prognosis. Therefore, we hypothesized that blockade of both CD73 and PD-L1 in combination with SBRT might improve antitumor efficacy in an orthotopic murine PDAC model.
We assessed the combination of systemic blockade of CD73/PD-L1 and local SBRT on tumor growth in primary pancreatic tumors, and investigated systemic antitumor immunity using a metastatic murine model bearing both orthotopic primary pancreatic tumor and distal hepatic metastases. Immune response was quantified by flow cytometric and Luminex analyses.
We demonstrated that blockade of both CD73 and PD-L1 significantly amplified the antitumor effect of SBRT, leading to superior survival. The triple therapy (SBRT+anti-CD73+anti-PD-L1) modulated tumor-infiltrating immune cells with increases of interferon-γCD8 T cells. Additionally, triple therapy reprogramed the profile of cytokines/chemokines in the tumor microenvironment toward a more immunostimulatory phenotype. The beneficial effects of triple therapy are completely abrogated by depletion of CD8 T cells, and partially reversed by depletion of CD4 T cells. Triple therapy promoted systemic antitumor responses illustrated by: (1) potent long-term antitumor memory and (2) enhanced both primary liver metastases control along with prolonged survival.
立体定向体部放疗（SBRT）诱导免疫原性细胞死亡，从而引发抗肿瘤免疫反应，但这部分反应会被免疫逃避过程所抵消，例如程序性死亡配体 1（PD-L1）和腺苷生成酶的上调。与正常胰腺组织相比，胰腺导管腺癌（PDAC）中 CD73 上调，而 PDAC 中 CD73 的高表达与肿瘤增大、晚期、淋巴结受累、转移、PD-L1 表达和预后不良有关。因此，我们假设在原位小鼠 PDAC 模型中，同时阻断 CD73 和 PD-L1 与 SBRT 联合使用可能会提高抗肿瘤疗效。
我们评估了系统阻断 CD73/PD-L1 与局部 SBRT 对原发性胰腺肿瘤生长的联合作用，并使用同时具有原位原发性胰腺肿瘤和远端肝转移的转移性小鼠模型研究了系统抗肿瘤免疫。通过流式细胞术和 Luminex 分析来量化免疫反应。
我们证明，同时阻断 CD73 和 PD-L1 显著增强了 SBRT 的抗肿瘤作用，从而提高了生存率。三联疗法（SBRT+抗 CD73+抗 PD-L1）通过增加干扰素-γ CD8 T 细胞来调节肿瘤浸润免疫细胞。此外，三联疗法还使肿瘤微环境中的细胞因子/趋化因子谱向更具免疫刺激性的表型转变。通过耗竭 CD8 T 细胞完全消除了三联疗法的有益作用，而通过耗竭 CD4 T 细胞部分逆转了这种作用。三联疗法通过以下方式促进了系统抗肿瘤反应：（1）强大的长期抗肿瘤记忆；（2）增强了对原发性肝转移的控制，并延长了生存时间。
