Fig. 4

Overview of cellular crosstalk driven by tumor derived exosomes and exosomal-PD-L1 in the tumor microenvironment: The cellular components of lung TME include immune cells, fibroblasts and epithelial cells with extracellular matrix and blood vessels. Among the many processes linked to the hallmarks of lung cancer, such as immune evasion, the establishment of a metastatic environment and angiogenesis, cancer cells secrete chemicals that regulate the TME and contribute to the progression of cancer. Exosomal PD-L1 (exo-PD-L1) is found not only in cancer cells but also in other immune cells, such as dendritic cells, macrophages, monocytes, natural killer cells, MDSCs.Other cells may also be sources of exo-PD-L1 which mediates functional PD-L1 transfer between cells and induces systemic immunosuppression microenvironments to facilitate metastasis. Tumor-derived exosomes (TEXs) are responsible for inducing PD-L1 expression in immune cells. This transpires through the upregulation of AKT/PTEN, MAPK and JAK/STAT signaling by regulatory proteins and microRNA. Cancer-associated fibroblasts (CAF) also express PD-L1 in response to interferon-γ (IFN-γ), a key activator of macrophages, natural killer cells and neutrophils. TEXs cause fibroblast activation (A), which leads to the secretion of soluble compounds that enhance PD-L1 expression in tumors and cause epithelial to mesenchymal transition phenotype (B). Similar to this, TEXs induce the PD-L1 to collaborate via vascular endothelial growth factor (VGEF) and alter angiogenesis (C) to sustain TME. The immune evasion is facilitated by pro-tumorigenic T regulatory (T reg) (D). Exosomal PD-L1 inhibits T cell activation by stimulating the production of CD8 + cytotoxic T lymphocytes, often known as CTLs. These lymphocytes target tumor cells and trigger apoptosis through their cytotoxic activities, a cytotoxic effect of CD8 + T lymphocytes which can be inhibited by exo-PD-L1. High concentrations of PD-L1 in exosomes can lead to apoptosis in activated CD8 + T lymphocytes. Figure created with BioRender.com