PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function

Sep 22, 2026

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PD-L2 is a key immune checkpoint ligand whose contribution to tumor immune escape remains insufficiently defined. The study demonstrates that renal clear cell carcinoma cells secrete PD-L2 via exosomes, increasing regulatory T cells while reducing cytotoxic CD8+ T cells. This shift in immune cell balance promotes tumor growth and metastasis in ccRCC. Methods include exosome collection from primary tumor cells and extensive in vitro and in vivo experimental characterization.

LanguageEnglish

CategoryHealthcare

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Pages9

Reading Time23 min

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Introduction

Materials and Methods

Cell lines, clinical specimens, and mice

Plasmids and antibodies

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN PD-L2 of tumor-derived exosomes mediates the immune escape of cancer cells via the impaired T cell function Tongfeng Liu 1,2, Shuwen Cheng2,3, Bo Peng2,4, Haojing Zang2,5, Xiaofeng Zhu 1,2, Xuetong Wang2,4, Xujie Zhao2, Yinmin Gu 2, Yongbo Pan2,6, Hongbo Hu 7 ✉ and Shan Gao 2 ✉ © The Author(s) 2024 INTRODUCTION Immune checkpoints play a vital role in mediating the escape of tumor cells for immunosurveillance [1] . The programmed cell death 1 (PD-1) receptor is one of the crucial immune checkpoint molecules which dampens immune responses via engagements with its two ligands, PD-1 ligand 1 (PD-L1) and PD-L2 expressed by cancer cells [2] . Especially PD-1/PD-L1 axis has been widely studied in various cancer types, and found to promote the immune escape of tumor cells [3, 4]. Targeting this axis has also demonstrated some beneﬁts for several cancer patients [5] . However, the potential function of PD-L2 in immune escape of tumor cells has been poorly studied. Moreover, the expression regulation of PDCD1/PDCD1LG1 that respectively encodes PD-1/PD-L1 has been studied in multiple levels including transcription, translation, post-transcription, and post-translation etc. [6–8]. The regulation of PDCD1LG2 encoding PD-L2 expression is incompletely understood. Extracellular vesicles (EVs) are broadly classiﬁed into exosomesand microvesicles (MVs) based on their different size, as important mediators of extracellular communication to regulate a diverse range of biological processes, including the immune system [9, 10] . Exosome is considered 30-200 nm in diameter, while MV is suggested as 200–1000 nm in diameter. Exosomes derived from tumor cells (TDEs) are essential for regulation of various cancer progression, including metastasis and immune escape [9, 11] . Whether PD-L2 is carried by TDEs to mediate immune escape remains elusive. In this study, we demonstrate that renal clear cell carcinoma (ccRCC) cells secrete PD-L2 via exosomes, which promotes growth and metastasis of ccRCC tumors via the increased regulatory T (Treg) cells and the decreased cytotoxic CD8+ T (CTL) cells. MATERIALS AND METHODS Cell lines, clinical specimens, and mice 786-O, 769-P, ACHN and Caki-1 cells were maintained in RPMI1640 medium (Gibco, Cat\#11875119) supplemented with 10% FBS (Gibco, Cat\#10099158) . HK2 cells were maintained in DMEM/F-12 medium (Gibco, Cat\#11330032) containing 10% FBS. Renca cells were maintained in RPMI1640 medium supplemented with 10% FBS, 1% Sodium Pyruvate (Gibco, Cat\#11360070) and 1 × MEM Non-Essential Amino Acids Solution (NEAA) (Gibco, Cat\#11140035) . The human embryonic kidney HEK293T cells were cultured in DMEM (Gibco, Cat\#11965092) supplemented with 10% FBS. These cell lines except Renca were purchased from the Shanghai Cell Bank Type Culture Collection Committee (Shanghai, China), and veriﬁed by short tandem repeat assays for their identiﬁcation. Renca cell line was from American Type Culture Collection. The PD-1 KO Jurkat cell line used in this study was constructed in our previous study [12] . Primary tumor cells separated from ccRCC tissues were cultured in RPMI1640 medium supplemented with 10% exosome-depleted FBS (Gibco, Cat\#A27208-03), 1% Sodium Pyruvate and 1×MEM NEAA to collect exosomes. These cells were cultured at 37 °C in a humidiﬁed incubator with 5% CO2 and regularly tested negative for Mycoplasma contamination. The pathologically diagnosed tissues (KIRC n = 9, COAD n = 3, PRADn = 6, LUAD n = 4) were obtained from ZhongDa Hospital Southeast 1Medical College, Guizhou University, Guiyang, China. 2Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing, China. 3Medical School of Nanjing University, Nanjing, China. 4School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. 5Depar

FAQs

What is the main question addressed about PD-L2 in this study?

The study investigates whether PD-L2 carried by tumor-derived exosomes contributes to immune escape by impairing T cell function.

How do tumor-derived exosomes affect T cells in ccRCC?

Exosome-mediated PD-L2 promotes regulatory T cell increase and decreases cytotoxic CD8+ T cells, supporting immune escape.

What are the observed effects on ccRCC tumors?

PD-L2 secretion via exosomes enhances ccRCC tumor growth and metastasis.

Sep 22, 2026

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