Exosomes and Immune Response in Cancer: Friends or Foes?

Abstract

Exosomes are a type of extracellular vesicle whose study has grown exponentially in recent years. This led to the understanding that these structures, far from being inert waste by-products of cellular functioning, are active players in intercellular communication mechanisms, including in the interactions between cancer cells and the immune system. The deep comprehension of the crosstalk between tumors and the immune systems of their hosts has gained more and more importance, as immunotherapeutic techniques have emerged as viable options for several types of cancer. In this review, we present a comprehensive, updated, and elucidative review of the current knowledge on the functions played by the exosomes in this crosstalk. The roles of these vesicles in tumor antigen presentation, immune activation, and immunosuppression are approached as the relevant interactions between exosomes and the complement system. The last section of this review is reserved for the exploration of the results from the first phase I to II clinical trials of exosomes-based cell-free cancer vaccines.

Keywords: cancer; clinical trials as topic; exosomes; extracellular vesicles; immune response.

Figure 1

Mechanisms used by exosomes to influence target cells. (A) Direct interaction between surface receptors on the exosome and on the target cell. (B) Cleavage of surface receptors on the exosome with subsequent interaction between the receptor fragments and receptors on the target cell. (C) Fusion of the exosome membrane with the plasma membrane of the target cell with release of the exosomal cargo into the cytoplasm of the cell. (D) Internalization of the whole exosome through phagocytosis.

Figure 2

Pathways for T cell activation by dendritic cell (DC)-derived exosomes. (A) Peptide MHC class II complexes (pMHC II) can be transferred to DC, and then exposed on the cell surface (cross-dressing). (B) Peptides can be used by DC, which load them onto their own endogenous MHC class II molecules, subsequently presenting them at their surface. Both these pathways (A,B) allow for the activation of CD4⁺ T cells. (C) Peptide MHC class I complexes (pMHC I) can directly interact and activate CD8⁺ T cells in a DC-independent manner.

Figure 3

Mechanisms used by tumor-derived exosomes to suppress immune responses. (A) Exosomes bearing apoptosis-inducing ligands, such as Fas ligand, TNF-related apoptosis-inducing ligand or, in the case of Th1 cells, galectin 9, can initiate T cell apoptosis. Exosomes also inhibit IL-2-dependent CD8⁺ T cell activation. (B) Exosomes bearing TGF-β1 can also disrupt IL-2 signaling to natural killer (NK) cells, thus inhibiting NK cell activation, cytotoxicity, and proliferation. The expression of the NKG2D receptor on NK cells can also be diminished by exosomes carrying NKG2D ligands, thus reducing NK cell ability to recognize malignant cells. (C) Exosomes can reduce the expression of toll-like receptor 4 and inhibit the transcription of MHC class II genes in dendritic cells, through the transference of different types of microRNA.