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PDL1‐positive exosomes suppress antitumor immunity by inducing tumor‐specific CD8+ T cell exhaustion during metastasis
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PDL1‐positive exosomes suppress antitumor immunity by inducing tumor‐specific CD8+ T cell exhaustion during metastasis
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PDL1‐positive exosomes suppress antitumor immunity by inducing tumor‐specific CD8+ T cell exhaustion during metastasis
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Journal Article
PDL1‐positive exosomes suppress antitumor immunity by inducing tumor‐specific CD8+ T cell exhaustion during metastasis
2021
Overview
Metastasis is the main cause of death in individuals with cancer. Immune checkpoint blockade (ICB) can potentially reverse CD8+ cytotoxic T lymphocytes (CTLs) dysfunction, leading to significant remission in multiple cancers. However, the mechanism underlying the development of CTL exhaustion during metastatic progression remains unclear. Here, we established an experimental pulmonary metastasis model with melanoma cells and discovered a critical role for melanoma‐released exosomes in metastasis. Using genetic knockdown of nSMase2 and Rab27a, 2 key enzymes for exosome secretion, we showed that high levels of effector‐like tumor‐specific CD8+ T cells with transitory exhaustion, instead of terminal exhaustion, were observed in mice without exosomes; these cells showed limited inhibitory receptors and strong proliferation and cytotoxicity. Mechanistically, the immunosuppression of exosomes depends on exogenous PD‐L1, which can be largely rescued by pretreatment with antibody blockade. Notably, we also found that exosomal PD‐L1 acts as a promising predictive biomarker for ICB therapies during metastasis. Together, our findings suggest that exosomal PD‐L1 may be a potential immunotherapy target, suggesting a new curative therapy for tumor metastasis. We demonstrate a crucial role for tumor‐released exosomes in promoting metastatic progression. We provide extensive evidence that exosomes from tumor cells act alone as contributors to driving tumor‐specific CD8+ T cell exhaustion in vivo. We also find that exosomal PD‐L1 acts as a promising predictive biomarker for ICB therapies during metastasis.
Publisher
John Wiley & Sons, Inc,John Wiley and Sons Inc
Subject
/ Aged
/ Animals
/ Antigens
/ B7-H1 Antigen - antagonists & inhibitors
/ Biomarkers, Tumor - metabolism
/ Cancer
/ Exosomes
/ Female
/ Humans
/ immune checkpoint blockade therapies
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Lung Neoplasms - drug therapy
/ Male
/ Melanoma
/ Mice
/ Original
/ Plasma
/ rab27 GTP-Binding Proteins - deficiency
/ rab27 GTP-Binding Proteins - genetics
/ Signal Transduction - drug effects
/ Signal Transduction - genetics
/ Sphingomyelin Phosphodiesterase - deficiency
/ Sphingomyelin Phosphodiesterase - genetics
/ T cells
/ T-Lymphocytes, Cytotoxic - immunology
