Immunoregulatory Roles of Extracellular Vesicles and Associated Therapeutic Applications in Lung Cancer

Abstract

Lung cancer represents a fatal condition that has the highest morbidity and mortality among malignancies. The currently available treatments fall short of improving the survival and quality of life of late-stage lung cancer patients. Extracellular vesicles (EVs) secreted by tumors or immune cells transport proteins, lipids, and nucleic acids to other cells, thereby mediating immune regulation in the tumor microenvironment. The cargo carried by EVs vary by cellular state or extracellular milieu. So far, multiple studies have suggested that EVs from lung tumor cells (TEVs) or immune cells promote tumor progression mainly through suppressing antitumor immunity. However, modified or engineered EVs can be used as vaccines to elicit antitumor immunity. In addition, blocking the function of immunosuppressive EVs and using EVs carrying immunogenic medicine or EVs from certain immune cells also shows great potential in lung cancer treatment. To provide information for future studies on the role of EVs in lung cancer immunity, this review focus on the immunoregulatory role of EVs and associated treatment applications in lung cancer.

Keywords: extracellular vesicles; immunostimulation; immunosuppression; lung cancer; therapeutic application.

FIGURE 1

The suppressive roles of EVs in lung cancer immunity. Lung tumor–derived exosomes and microparticles can suppress antitumor immunity in various ways. Activated T-cells release microparticles, which induce their own death via Fas/FasL signaling. TEXs, Lung tumor-derived exosomes; TMPs, tumor-derived microparticles; LMPs, T-lymphocyte-derived microparticles; TAN, tumor-associated neutrophil; AICD, activation-induced cell death; MDSCs, Myeloid-derived suppressor cells; M1/2, macrophages subtype 1/2. Figure created with BioRender.com.

FIGURE 2

The stimulatory roles of EVs in lung cancer immunity. (a) Heat stressed, (b) Rab27a overexpressed, and (c) CD40L overexpressed lung cancer cell–derived exosomes (TEXs) can activate DC maturation and arouse specific antitumor immunity. (d) Activated dendritic cell–derived exosomes (DEXs) can present antigens to T-cells directly or by transferring pMHC to other immature dendritic cells and amplifing this antigen-presentation effect. TCR, T-cell receptor. Figure created with BioRender.com.

FIGURE 3

The applications of EVs in lung cancer therapy. (A) Modified lung cancer cells, dendritic cells, or embryonic stem cell–derived extracellular vesicles can be used to stimulate antitumor immunity as vaccines. Modified T-cells or macrophage-derived extracellular vesicles can potentially inhibit proliferation of lung cancer cells. (B) Blocking the release of exosomes from lung cancer cells (TEXs) or neutralizing the immunosuppressive molecules on TEXs are potentially effective antitumor ways. ?, uncertain; MAGE, melanoma antigen gene; GM-CSF, granulocyte-macrophage colony-stimulating factor; MTX, methotrexate; OVs, Oncolytic virus; TMPs, lung tumor-derived microparticles; TEVs, EVs from lung tumor cells; TEXs, Lung cancer-derived exosomes; DEXs, exosomes from dendritic cells; ESEVs, EVs from embryonic stem cells; LMPs, T-lymphocyte-derived microparticles; MEXs, exosomes derived from macrophages; DMA, Dimethyl amiloride; HSP72, Heat Shock Protein 72; TLR2, toll-like receptor 2. Figure created with BioRender.com.