Blockade of PD-1/PD-L1 Pathway Enhances the Antigen-Presenting Capacity of Fibrocytes
Blockade of PD-1/PD-L1 Pathway Enhances the Antigen-Presenting Capacity of Fibrocytes
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DOI：
10.4049/jimmunol.2000909
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发表时间：
2021-03-15
影响因子：
4.4
通讯作者：
Nishioka, Yasuhiko
中科院分区：
文献类型：
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作者：
Afroj, Tania;Mitsuhashi, Atsushi;Nishioka, Yasuhiko
纤维细胞是一种独特的产生胶原的单核细胞衍生细胞群，参与伤口愈合以及纤维化疾病。最近，纤维细胞已被揭示在肿瘤微环境中发挥作用，特别是在抗血管生成治疗下。此外，在临床环境中，已经开发了具有免疫检查点抑制剂和抗血管生成剂的组合癌症免疫疗法用于各种癌症，尽管免疫学背景尚不清楚。在目前的研究中，我们的目的是确定纤维细胞在免疫检查点抑制剂治疗诱导的肿瘤免疫中的功能。分别从PBMC和肺产生人和鼠纤维细胞。流式细胞仪检测纤维细胞表面共刺激分子和抑制分子的表达。用H-3-胸苷掺入法检测了MLR中纤维细胞对CD 8（+）T细胞的刺激作用。纤维细胞表达CD 80（低）和CD 86（高）作为共刺激分子，表达PD-L1（高），但不表达PD-L2作为共抑制分子。在没有任何刺激的情况下，纤维细胞强烈增强了小鼠和人类中CD 8（+）T细胞的增殖。用抗CD 86和抗CD 54抗体处理可抑制纤维细胞诱导的CD 8（+）T细胞的生长。抗PD-L1抗体进一步增强了CD 8（+）T细胞的增殖，甚至在具有OT-1 Rag（-/-）的OVA特异性MLR小鼠中也是如此。重要的是，来源于肺腺癌或小鼠MC 38肿瘤患者PBMC的纤维细胞在PD-L1阻断的情况下增强了CD 8（+）T细胞的增殖。这些结果表明，当PD-L1/PD-1阻断进一步增强活性时，浸润肿瘤部位的纤维细胞可能在CD 8（+）T细胞介导的抗肿瘤免疫中发挥作用。
Fibrocytes, a distinct population of collagen-producing, monocyte-derived cells, are involved in wound healing as well as fibrotic diseases. Recently, fibrocytes have been revealed to play a role in the tumor microenvironment, particularly under antiangiogenic therapy. In addition, combination cancer immunotherapy with immune checkpoint inhibitor and antiangiogenic agents have been developed for various cancers in the clinical setting, although the immunological background is not clear. In the current study, we aimed to determine the function of fibrocytes in tumor immunity induced by immune checkpoint inhibitor therapy. Human and murine fibrocytes were generated from PBMCs and lungs, respectively. The expression of costimulatory and inhibitory molecules on fibrocytes was examined by flow cytometry. The stimulation of CD8(+) T cells by fibrocytes was examined in MLRs with a H-3-thymidine incorporation assay. Fibrocytes expressed CD80(low) and CD86(high) as a costimulatory molecule, and expressed PD-L1(high), but not PD-L2, as a coinhibitory molecule. Without any stimulation, fibrocytes strongly enhanced the proliferation of CD8(+) T cells in mice and humans. Treatment with anti-CD86 and -CD54 Abs inhibited the growth of CD8(+) T cells induced by fibrocytes. Anti-PD-L1 Ab further enhanced the proliferation of CD8(+) T cells, even in the OVA-specific MLR with OT-1Rag(-/-) mice. Importantly, fibrocytes derived from PBMCs of patients with lung adenocarcinoma or murine MC38 tumors augmented the proliferation of CD8(+) T cells with PD-L1 blockade. These results suggest that fibrocytes infiltrating tumor sites may play a role in the antitumor immunity mediated by CD8(+) T cells when the activity is further enhanced by PD-L1/PD-1 blockade.