Oral Cancer Stem Cell-Derived Small Extracellular Vesicles Promote M2 Macrophage Polarization and Suppress CD4+ T-Cell Activity by Transferring UCA1 and Targeting LAMC2

Abstract

Cancer-derived small extracellular vesicles (sEVs) are emerging as crucial mediators of intercellular communication between cancer cells and M2-tumor-associated macrophages (M2-TAMs) via transferring lncRNAs. We previously reported that miR-134 blocks the expression of its targeting protein LAMC2 via the PI3K/AKT pathway and inhibits cancer stem cell (CSC) migration and invasion in oral squamous cell carcinoma (OSCC). This study hypothesize that OSCC-CSC-derived small extracellular vesicles (OSCC-CSC-sEVs) transfer a ceRNA of miR-134 and consequently promote M2 macrophage polarization by targeting LAMC2 via the PI3K/AKT pathway through in vitro and in vivo experiment methods. The results showed that sEVs derived from CD133+CD44+ OSCC cells promoted M2 polarization of macrophages by detecting several M2 macrophage markers (CD163, IL-10, Arg-1, and CD206+CD11b+). Mechanistically, we revealed that the lncRNA UCA1, by binding to miR-134, modulated the PI3K/AKT pathway in macrophages via targeting LAMC2. Importantly, OSCC-CSC-sEV transfer of UCA1, by targeting LAMC2, promoted M2 macrophage polarization and inhibited CD4+ T-cell proliferation and IFN-γ production in vitro and in vivo. Functionally, we demonstrated that M2-TAMs, by transferring exosomal UCA and consequently targeting LAMC2, enhanced cell migration and invasion of OSCC in vitro and the tumorigenicity of OSCC xenograft in nude mice. In conclusion, our results indicated that OSCC-CSC-sEV transfer of UCA1 promotes M2 macrophage polarization via a LAMC2-mediated PI3K/AKT axis, thus facilitating tumor progression and immunosuppression. Our findings provide a new understanding of OSCC-CSC molecular mechanisms and suggest a potential therapeutic strategy for OSCC through targeting CSC-sEVs and M2-TAMs.

Emerging functions and applications of exosomes in oral squamous cell carcinoma

“…Previous studies indicated that the OSCC/CAFs derived exosomes can be internalized by OSCC cells, and then promote the growth, migration, and invasion of tumor cells by activating PI3K/AKT 16 and MAPK/ERK 17 pathways (Figure 2B). For instance, the highly expressed miRNA-382-5p in CAFs can be transported to OSCC cells via exosomes, thus promoting the invasion of OSCC.…”

“…22 However, relevant studies have also shown that exosomes were involved in immunosuppression. 23 Exosomes extracted from plasma of patients with head and neck cancer could effectively inhibit proliferation of CD4 + T cells, induce apoptosis of CD8 + T cells, accelerate the immunosuppressive ability of regulatory T cells (Treg cells), and weaken the cytotoxicity of natural killer (NK) cells 16 (Figure 2C).…”

“…Promotion of the growth, migration, and invasion of tumor cells CAFs PI3K/AKT pathway, MAPK/ERK pathway [16,17] Promoting the invasion of OSCC CAFs High expression of miRNA-382-5p [18] Contributing to the malignant progression of OSCC CAFs Lack of miRNA-34a-5p [19] Suppressing tumor growth of OSCC CAFs TRAP1 [20] Inhibiting proliferation of CD4 + T cells, inducing apoptosis of CD8 + T cells, accelerating the immunosuppressive ability of regulatory T cells (Treg cells), and weakening the cytotoxicity of natural killer (NK) cells Plasma of patients with head and neck cancer - [ 16] Transforming macrophages into M1-like OSCC p38, Akt and SAPK/JNK pathway [27] Promoting proliferation and anti-tumor effect of γδT cell OSCC Heat shock proteins 70 (HSP70) [29] Inducing the proliferation and migration of human umbilical vein endothelial cells (HUVEC) OSCC - [31] exosomes derived from OSCC on γδT cells were eliminated. The OSCC-derived exosomes could be internalized by myeloid-derived suppressor cells, and then inhibiting the activity of γδT cells and reversing the immune activation effect of exosomes in normoxic environment.…”

Extracellular Vesicles as Biomarkers in Head and Neck Squamous Cell Carcinoma: From Diagnosis to Disease-Free Survival

“…EVs could envelop and transport lncRNA from tumor cells to target cells, consequently influencing the expression of miRNA and changing the tumor microenvironment (TME) [ 142 ]. One of the most representative lncRNAs was HOTTIP, and it caused various changes according to its origin: the M1 macrophage-derived exosomal lncRNA HOTTIP proved to strongly suppressed tumor progression via the upregulation of the TLR5/NF-κB pathway [ 143 ]; however, when it was secreted by cancer stem cells in OSCC, it then promoted M2 macrophage polarization, inhibited CD4+ T-cell proliferation and IFN-γ production, and facilitated tumor progression and immunosuppression via the LAMC2-mediated PI3K/AKT pathway [ 144 ].…”

Harnessing cancer stem cell-derived exosomes to improve cancer therapy

“…Other ncRNAs secreted by CSCs could also be potent regulators involved in TME; glioma CSCs release exosomes carrying lncRNA MALAT1, which induces secretion of IL-6 and TNF-α from LPS-stimulated microglia cells. Oral squamous cell carcinoma (OSCC)-CSC-derived EVs transferred miR-134 and consequently promoted M2 macrophage polarization by targeting LAMC2 via the PI3K/AKT pathway in vitro and in vivo [ 112 ]. M2 macrophage-derived exosomal miR-31-5p can inhibit the tumor suppressor LATS2 gene and facilitate the progression of OSCC via inhibiting the Hippo signaling pathway [ 113 ].…”