Activated T cell-derived exosomal PD-1 attenuates PD-L1-induced immune dysfunction in triple-negative breast cancer

Yufan Qiu,Jin Zhang,Linlin Sun,Yi Yang,Jung-Mao Hsu,Zhou Jiang,Chia-Wei Li,Riyao Yang,Dihua Yu,Chunxiao Liu,Mien-Chie Hung,Yongkun Wei

doi:10.1038/s41388-021-01896-1

Abstract

Programmed cell death 1 (PD-1) is widely expressed in tumor-infiltrating lymphocytes (TILs) of triple-negative breast cancer (TNBC). As a dominant inhibitory immune checkpoint (ICP) receptor, cell surface PD-1 is well-known to transduce negative signaling of effector T cell activity during cell–cell contact. However, despite its well-documented inhibitory effects, higher PD-1 expression in TILs is significantly associated with longer survival in TNBC patients. This phenomenon raises an interesting question whether PD-1 harbors positive activity to enhance anti-tumor immunity. Here, we show that PD-1 is secreted in an exosomal form by activated T cells and can remotely interact with either cell surface or exosomal programmed death-ligand 1 (PD-L1), induce PD-L1 internalization via clathrin-mediated endocytosis, and thereby prevent subsequent cellular PD-L1: PD-1 interaction, restoring tumor surveillance through attenuating PD-L1-induced suppression of tumor-specific cytotoxic T cell activity. Our results, through revealing an anti-PD-L1 function of exosomal PD-1, provide a positive role to enhance cytotoxic T cell activity and a potential therapeutic strategy of modifying the exosome surface with membrane-bound inhibitory ICP receptors to attenuate the suppressive tumor immune microenvironment.

Highlights

Triple-negative breast cancer (TNBC) is a group of highly heterogeneous tumors with diverse biological behavior and clinical outcomes
Exosomes carrying membrane-bound Programmed cell death 1 (PD-1) are released by activated T cells To study the biological implications of Exo-PD-1 using the proper model, we first isolated exosomes derived from peripheral blood mononuclear cells (PBMCs)-derived T cells and Jurkat-T cells
To analyze the expression pattern of immune checkpoints carried by T cell exosomes in a non-biased approach, we used an ICP array to test the exosomes secreted from T-cell-receptor (TCR)-non-activated and activated T cells (Fig. 1B and Supplementary Fig. 1)

Summary

Introduction

Triple-negative breast cancer (TNBC) is a group of highly heterogeneous tumors with diverse biological behavior and clinical outcomes. Programmed cell death 1 (PD-1) is one of the co-inhibitory immune checkpoint (ICP) receptors induced upon T cell activation and widely expressed (70.3%) in TILs [5]. PD-1 expression is significantly associated with longer disease-free survival and overall survival in patients with TNBC [5]. Consistent results have shown that high PDCD1 gene transcription levels within TNBC tumors and high numbers of PD-1-positive immune infiltrates are associated with significantly increased disease-free survival [8]. Together, these findings raised an interesting question: whether PD-1 on T cells might somehow associate with possible functions in restricting the immune evasion of tumor cells aside from the conventional immunosuppressive activity?

Methods

Results

Conclusion