Exosomes are promising tools for improving cancer care, but conversely may also contribute to tumor progression. Researchers at MD Anderson Cancer Center highlight recently discovered roles of exosomes in modulating immune responses in cancer, with emphasis on exosomal surface proteins and on RNA and DNA content. They also discuss how exosomes could be exploited as biomarkers and delivery vehicles in cancer therapy.
Exosomes from cancer cells modulate immune responses and can co-opt local and distant normal cells to further promote tumor progression
(1) Cancer cells (a) release exosomes (b) that carry damage-associated molecular patterns (DAMPs) such as DNA and RNA to myeloid cells (c) which activate the intracellular virus-sensing pathways cyclic GMP-AMP synthase—stimulator of interferon genes (cGAS-STING), retinoic acid-inducible gene I (RIG-I), and Absent in melanoma 2 (AIM-2), and stimulate the production of inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-8, and IL-1β. Conversely, activated epidermal growth factor receptor (EGFR) on the surface of breast cancer exosomes (b) can suppress antiviral innate immunity in dendritic cells (c) through the kinase MEKK2, which prevents activation of interferon regulatory transcription factor 3 (IRF3) and type 1 interferon (IFN) expression. Immune cells (c) such as B lymphocytes produce major histocompatibility complex (MHC) class I- and II-containing exosomes that can have antitumor effects through activation of CD8+ T cells, for example . (2) Cancer cells (a) can also indirectly alter immune cells (c) through the integrin-based interaction of exosomes (b) with surrounding and distant normal fibroblasts (d) and epithelial cells. (3) Subsequently, these interactions can promote tumor growth and metastasis by driving inflammation of myeloid cells (c) through antiviral immune mechanisms, involving activation of the pattern recognition receptor (PRR) RIG-I in the cancer cells (a). gDNA, genomic DNA; MVB, multivesicular body