PD-L1/L2 protein levels rapidly increase on monocytes via trogocytosis from tumor cells in classical Hodgkin lymphoma.,Leukemia

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PD-L1/L2 protein levels rapidly increase on monocytes via trogocytosis from tumor cells in classical Hodgkin lymphoma.
Leukemia ( IF 12.8 ) Pub Date : 2020-02-24 , DOI: 10.1038/s41375-020-0737-9
Masaharu Kawashima _{1,

2} , Joaquim Carreras ₃ , Hiroshi Higuchi _{1,

4} , Ryutaro Kotaki ₁ , Takahiro Hoshina _{1,

5} , Kazuki Okuyama ₁ , Naoto Suzuki _{1,

6,

7} , Masatoshi Kakizaki ₁ , Yuji Miyatake ₁ , Kiyoshi Ando ₈ , Masafumi Nakayama ₉ , Shinjiro Umezu ₁₀ , Ryouichi Horie ₁₁ , Yuriko Higuchi ₁₂ , Koko Katagiri ₆ , Susumu Goyama ₅ , Toshio Kitamura ₅ , Kenji Chamoto ₁₃ , Shingo Yano ₂ , Naoya Nakamura ₃ , Ai Kotani _{1,

14,

15}

Affiliation

Department of Hematological Malignancy, Institute of Medical Science, Tokai University, Isehara, Kanagawa, Japan.
Division of Clinical Oncology and Hematology, Jikei University School of Medicine, Minato-ku, Tokyo, Japan.
Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Research Institute of Science and Technology, Tokai University, Hiratsuka, Kanagawa, Japan.
Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
Department of Biosciences, School of Science, Kitasato University, Sagamihara, Kanagawa, Japan.
Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Aoba-ku, Sendai, Japan.
Department of Modern Mechanical Engineering, Waseda University, Shinjuku-ku, Tokyo, Japan.
Division of Hematology, Department of Laboratory Sciences, School of Allied Health Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan.
AMED-PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan.

In classical Hodgkin lymphoma (cHL)-characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells-tumor-associated macrophages (TAMs) play a pivotal role in tumor formation. However, the significance of direct contact between HRS cells and TAMs has not been elucidated. HRS cells and TAMs are known to express PD-L1, which leads to PD-1+ CD4+ T cell exhaustion in cHL. Here, we found that PD-L1/L2 expression was elevated in monocytes co-cultured with HRS cells within 1 h, but not in monocytes cultured with supernatants of HRS cells. Immunofluorescence analysis of PD-L1/L2 revealed that their upregulation resulted in membrane transfer called "trogocytosis" from HRS cells to monocytes. PD-L1/L2 upregulation was not observed in monocytes co-cultured with PD-L1/L2-deficient HRS cells, validating the hypothesis that there is a direct transfer of PD-L1/L2 from HRS cells to monocytes. In the patients, both ligands (PD-L1/L2) were upregulated in TAMs in contact with HRS cells, but not in TAMs distant from HRS cells, suggesting that trogocytosis occurs in cHL patients. Taken together, trogocytosis may be one of the mechanisms that induces rapid upregulation of PD-L1/L2 in monocytes to evade antitumor immunity through the suppression of T cells as mediated by MHC antigen presentation.

中文翻译：

在经典霍奇金淋巴瘤中，单核细胞上的PD-L1 / L2蛋白水平通过肿瘤细胞的吞噬作用迅速增加。

在经典的霍奇金淋巴瘤（cHL）中，以霍奇金和里德-斯特恩伯格（HRS）的存在为特征，肿瘤相关的巨噬细胞（TAM）在肿瘤形成中起关键作用。但是，尚未阐明HRS细胞与TAM之间直接接触的重要性。已知HRS细胞和TAM表达PD-L1，导致cHL中PD-1 + CD4 + T细胞衰竭。在这里，我们发现PD-L1 / L2表达在1小时内与HRS细胞共培养的单核细胞中升高，但在与HRS细胞上清液培养的单核细胞中没有升高。PD-L1 / L2的免疫荧光分析表明，它们的上调导致膜转移，称为“转胞吞作用”，从HRS细胞转移到单核细胞。在与PD-L1 / L2缺失的HRS细胞共培养的单核细胞中未观察到PD-L1 / L2上调，验证了PD-L1 / L2从HRS细胞直接转移到单核细胞的假设。在患者中，两种配体（PD-L1 / L2）在与HRS细胞接触的TAM中均上调，但在与HRS细胞远离的TAM中均未上调，这表明在cHL患者中发生了光吞作用。综上所述，光吞作用可能是诱导单核细胞PD-L1 / L2快速上调以通过抑制T细胞（如MHC抗原呈递介导的）逃避抗肿瘤免疫的机制之一。

更新日期：2020-02-24

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