Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
J Immunother Cancer. 2020 Apr;8(1). doi: 10.1136/jitc-2019-000474.
Type 1 conventional dendritic cells (cDC1s) possess efficient antigen presentation and cross-presentation activity, as well as potent T cell priming ability. Tissue-resident cDC1s (CD103 cDC1s in mice, CD141 cDC1s in humans) are linked with improved tumor control, yet the efficacy of immunotherapy using this population is understudied.
We generated murine CD103 cDC1s in vitro and examined their expression of cDC1-related factors, antigen cross-presentation activity, and accumulation in tumor-draining lymph nodes (TdLNs). The antitumor efficacy of the in vitro-generated CD103 cDC1s was studied in murine melanoma and osteosarcoma models. We evaluated tumor responses on vaccination with CD103 cDC1s, compared these to vaccination with monocyte-derived DCs (MoDCs), tested CD103 cDC1 vaccination with checkpoint blockade, and examined the antimetastatic activity of CD103 cDC1s.
In vitro-generated CD103 cDC1s produced cDC1-associated factors such as interleukin-12p70 and CXCL10, and demonstrated antigen cross-presentation activity on stimulation with the toll-like receptor 3 agonist polyinosinic:polycytidylic acid (poly I:C). In vitro-generated CD103 cDC1s also migrated to TdLNs following poly I:C treatment and intratumoral delivery. Vaccination with poly I:C-activated and tumor antigen-loaded CD103 cDC1s enhanced tumor infiltration of tumor antigen-specific and interferon-γ CD8 T cells, and suppressed melanoma and osteosarcoma growth. CD103 cDC1s showed superior antitumor efficacy compared with MoDC vaccination, and led to complete regression of 100% of osteosarcoma tumors in combination with CTLA-4 antibody-mediated checkpoint blockade. In vitro-generated CD103 cDC1s effectively protected mice from pulmonary melanoma and osteosarcoma metastases.
Our data indicate an in vitro-generated CD103 cDC1 vaccine elicits systemic and long-lasting tumor-specific T cell-mediated cytotoxicity, which restrains primary and metastatic tumor growth. The CD103 cDC1 vaccine was superior to MoDCs and enhanced response to immune checkpoint blockade. These results indicate the potential for new immunotherapies based on use of cDC1s alone or in combination with checkpoint blockade.
1 型传统树突状细胞（cDC1）具有高效的抗原呈递和交叉呈递活性，以及强大的 T 细胞启动能力。组织驻留的 cDC1（小鼠中的 CD103 cDC1，人类中的 CD141 cDC1）与改善肿瘤控制有关，但使用该群体进行免疫治疗的疗效仍有待研究。
我们在体外生成了小鼠 CD103 cDC1，并研究了它们表达的 cDC1 相关因子、抗原交叉呈递活性以及在肿瘤引流淋巴结（TdLNs）中的积累。研究了体外生成的 CD103 cDC1 在小鼠黑色素瘤和骨肉瘤模型中的抗肿瘤功效。我们评估了用 CD103 cDC1 接种疫苗的肿瘤反应，将其与单核细胞衍生的树突状细胞（MoDC）接种疫苗进行比较，测试了 CD103 cDC1 接种疫苗与检查点阻断的结合，并研究了 CD103 cDC1 的抗转移活性。
体外生成的 CD103 cDC1 产生了白细胞介素-12p70 和 CXCL10 等 cDC1 相关因子，并在刺激 Toll 样受体 3 激动剂聚肌苷酸：聚胞苷酸（poly I:C）时表现出抗原交叉呈递活性。体外生成的 CD103 cDC1 在用 poly I:C 处理和肿瘤内递送后也迁移到 TdLNs。用 poly I:C 激活和肿瘤抗原负载的 CD103 cDC1 接种疫苗增强了肿瘤抗原特异性和干扰素-γ CD8 T 细胞的浸润，并抑制了黑色素瘤和骨肉瘤的生长。与 MoDC 疫苗接种相比，CD103 cDC1 显示出更好的抗肿瘤功效，并与 CTLA-4 抗体介导的检查点阻断联合导致 100%骨肉瘤肿瘤的完全消退。体外生成的 CD103 cDC1 有效地保护小鼠免受肺黑色素瘤和骨肉瘤转移的侵害。
我们的数据表明，体外生成的 CD103 cDC1 疫苗引发了全身性和持久的肿瘤特异性 T 细胞介导的细胞毒性，从而抑制了原发性和转移性肿瘤的生长。CD103 cDC1 疫苗优于 MoDC 并增强了对免疫检查点阻断的反应。这些结果表明，基于单独使用 cDC1 或与检查点阻断联合使用的新型免疫疗法具有潜力。
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