Abstract
Tumor-associated macrophages play a key role in promoting tumor progression by exerting an immunosuppressive phenotype associated with the expression of programmed cell death ligand 1 (PD-L1). It is well known that tumor-derived small extracellular vesicles (SEVs) affect the tumor microenvironment, influencing TAM behavior. The present study aimed to examine the effect of SEVs derived from colon cancer and multiple myeloma cells on macrophage functions. Non-polarized macrophages (M0) differentiated from THP-1 cells were co-cultured with SEVs derived from a colorectal cancer (CRC) cell line, SW480, and a multiple myeloma (MM) cell line, MM1.S. The expression of PD-L1, interleukin-6 (IL-6), and other inflammatory cytokines as well as of the underlying molecular mechanisms were evaluated. Our results indicate that SEVs can significantly upregulate the expressions of PD-L1 and IL-6 at both the mRNA and protein levels and can activate the STAT3 signaling pathway. Furthermore, we identified the TLR4/NF-kB pathway as a convergent mechanism for SEV-mediated PD-L1 expression. Overall, these preliminary data suggest that SEVs contribute to the formation of an immunosuppressive microenvironment.
Highlights
Tumor immunoescape is a well-known hallmark of cancer [1], and it is mainly caused by the activation of the programmed cell-death protein 1 (PD1)/programmed cell death ligand 1 (PD-L1) signaling pathway, which inhibits T cell-mediated antitumor responses [2,3,4]
We focused on analyzing the effects of colorectal cancer (CRC) and multiple myeloma (MM)-small extracellular vesicles (SEVs) on the modulation of PD-L1 in macrophages
We demonstrated that the expression of PD-L1 on macrophages is increased by CRC- and MM-SEV treatments
Summary
Tumor immunoescape is a well-known hallmark of cancer [1], and it is mainly caused by the activation of the programmed cell-death protein 1 (PD1)/PD-L1 signaling pathway, which inhibits T cell-mediated antitumor responses [2,3,4]. Different components of the tumor microenvironment can affect cancer progression, playing a key role in tumorpromoting immunoescape; among them, tumor-associated macrophages as well as tumorderived small extracellular vesicles (SEVs) represent key players in this process and are currently being explored as therapeutic targets [14,15,16]. Tumor-associated macrophages, characterized by M2-like phenotype, represent one of the most important immune cell types in the tumor microenvironment and play a key role in different aspects of cancer progression such as immunosuppression [19]. Kubota K. et al demonstrated that CD163+CD204+ tumor-associated macrophages promote T-cell apoptosis and immunosuppression via IL-10 and PD-L1, predicting unfavorable prognosis in oral squamous cell carcinoma patients [15]
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