Abstract
Inhibiting the programmed cell death ligand-1 (PD-L1)/programmed cell death receptor-1 (PD-1) signaling axis reinvigorates the antitumor immune response with remarkable clinical efficacy. Yet, low response rates limit the benefits of immunotherapy to a minority of patients. Recent studies have explored the importance of PD-L1 as a transmembrane protein in exosomes and have revealed exosomal PD-L1 as a mechanism of tumor immune escape and immunotherapy resistance. Exosomal PD-L1 suppresses T cell effector function, induces systemic immunosuppression, and transfers functional PD-L1 across the tumor microenvironment (TME). Because of its significant contribution to immune escape, exosomal PD-L1 has been proposed as a biomarker to predict immunotherapy response and to assess therapeutic efficacy. In this review, we summarize the immunological mechanisms of exosomal PD-L1, focusing on the factors that lead to exosome biogenesis and release. Next, we review the effect of exosomal PD-L1 on T cell function and its role across the TME. In addition, we discuss the latest findings on the use of exosomal PD-L1 as a biomarker for cancer immunotherapy. Throughout this review, we propose exosomal PD-L1 as a critical mediator of tumor progression and highlight the clinical implications that follow for immuno-oncology, discussing the potential to target exosomes to advance cancer treatment.
Highlights
The success of cancer immunotherapy highlights how the maintenance and expansion of malignancy strongly depend on immunosuppression [1]
We review the role of exosomal programmed cell death ligand-1 (PD-L1) in cancer immunotherapy; we discuss the immunological mechanisms by which exosomal PD-L1 is proposed to mediate immune escape and the clinical implications that follow for cancer treatment
The study of immune checkpoints in cancer has led to the development of novel therapeutic opportunities, such as PD-L1/programmed cell death receptor-1 (PD-1) blockade
Summary
The success of cancer immunotherapy highlights how the maintenance and expansion of malignancy strongly depend on immunosuppression [1]. Recent evidence suggests that adaptive cancer responses mediate changes in PD-L1 expression and subcellular localization, which have been associated with therapy failure [6]. It is known that exosomal PD-L1 elicits the same function as its cellular counterpart and binds with the same affinity to PD-1 and even to monoclonal antibodies against PD-L1 [14, 17]. In light of these findings, exosomal PD-L1 has been suggested as a primary mediator of immune escape and tumor progression, as well as a mechanism of therapy resistance. We review recent data on the use of exosomal PD-L1 as a predictive biomarker for immunotherapy and discuss potential therapeutic approaches that intend to target exosomes in the TME
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