Exosome secretion from hypoxic cancer cells reshapes the tumor microenvironment and mediates drug resistance

Abstract

Hypoxia is a common phenomenon in solid tumors as the poorly organized tumor vasculature cannot fulfill the increasing oxygen demand of rapidly expanding tumors. Under hypoxia, tumor cells reshape their microenvironment to sustain survival, promote metastasis, and develop resistance to therapy. Exosomes are extracellular vesicles secreted by most eukaryotic cells, including tumor cells. They are enriched with a selective collection of nucleic acids and proteins from the originating cells to mediate cell-to-cell communication. Accumulating evidence suggests that exosomes derived from tumor cells play critical roles in modulating the tumor microenvironment (TME). Hypoxia is known to stimulate the secretion of exosomes from tumor cells, thereby promoting intercellular communication of hypoxic tumors with the surrounding stromal tissues. Exosome-mediated signaling pathways under hypoxic conditions have been reported to cause angiogenesis, invasion, metastasis, drug resistance, and immune escape. Recently, the programmed cell death ligand-1 (PD-L1) has been reported to reside as a transmembrane protein in tumor exosomes. Exosomal PD-L1 was shown to suppress T cell effector function in the TME and cause drug resistance to immune checkpoint therapy. This review provides an update about the pivotal role of tumor-derived exosomes in drug resistance to chemotherapy and immunotherapy, particularly under hypoxic conditions. Emerging strategies that target the exosomes in the hypoxic TME to enhance the antitumor efficacy are discussed.

Keywords: Hypoxia; drug resistance; exosome; immunotherapy; non-coding RNA; tumor microenvironment.

Figure 1

Representative examples of exosome-mediated intercellular communication within the hypoxic TME driving cancer progression, chemoresistance, and immune suppression. (1) Cancer proliferation: Hypoxic cancer-secreted exosomes were enriched with miRNAs supporting cell survival (e.g., miR-210) in the neighboring cancer cells. (2) Drug resistance: Numerous ncRNAs (e.g., linc-RoR and miR-21) were transferred via exosomes from hypoxic and resistant cancer cells to sensitive cells and induced drug resistance. (3) Migration and invasion: exosomes containing various ncRNAs (including lncRNA UCA1 and miR-193-3p) facilitate cancer–cancer or cancer–stromal intercellular communication to stimulate migration and invasion by modulating EMT. (4) Angiogenesis: ncRNAs (including miR-23a and lncRNA UCA1) were enriched in the exosomes secreted from hypoxic tumor cells to promote tumor vascular endothelial cell proliferation and angiogenesis in HIF-1α-dependent or -independent pathway. (5) Immune suppression: Exosomes enriched with miRNAs (e.g., miR-23a and let-7a) and other immunosuppressive molecules (e.g., PD-L1 and TGF-β1) were secreted from hypoxic tumors to promote an immunosuppressive TME. TME: Tumor microenvironment.

Figure 2

Hypoxic tumor-secreted exosomes promote an immunosuppressive TME. Hypoxic tumor-secreted exosomes promote an immunosuppressive TME by interfering with several intracellular pathways and modulating immune accessory cells, including cytotoxic T cells, T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs), natural killer cells (NK), and tumor-associated macrophages (TAMs). (1) Inhibition of T cell proliferation; (2) stimulation of Treg differentiation; (3) induction of MDSCs; (4) impairment of NK cells; and (5) stimulation of M2 polarization of TAMs.