Colorectal cancer-derived extracellular vesicles containing HSP70 enhance macrophage phagocytosis by up-regulating MARCO expression

Colorectal cancer (CRC) is the third most common and second most deadly cancer in the world according to GLOBOCAN 2020 [1]. Nearly two million new cases and approximately one million deaths were estimated to occur in 2020 [1]. With the improvements in technology and equipment, especially the application of immunotherapy, the overall 5-year survival rate of CRC has reached 65% [2]. However, the prognosis of CRC patients with distant metastases is not satisfactory, and the 5-year survival rate is only 15% [2]. Therefore, it is necessary to further study the immunomodulatory mechanism of CRC to provide a theoretical basis for the development of new therapeutic targets.

Recently, many studies revealed that extracellular vesicles (EVs) are involved in mediating the intercellular crosstalk between tumor and immune cells in the tumor microenvironment (TME) [[3], [4], [5]]. EVs are a class of nanoparticles with bilayer lipid membranes that are naturally released by cells [6]. Based on diameter differences, EVs are usually classified into exosomes (50–150 nm), microvesicles (200–800 nm), and large EVs (≥1000 nm; such as apoptotic bodies) [7]. EVs contain a large number of molecular cargoes (such as miRNAs, proteins, and lipids) that have multiple functions [8]. Between CRC and immune cells, CRC can modulate the functional changes of immune cells via secreting EVs. For example, CRC-derived EVs (CRC-EVs) carrying miRNAs (miR-25–3p, miR-130b-3p, and miR-425–5p) induced macrophage M2 polarization through activating the PI3K/Akt signaling pathway [9]; CRC-EVs induced PD-L1 expression in TAMs to promote tumor evasion [10]; EVs from CRC stem cells promote neutrophil survival by up-regulating IL-1β expression, thus facilitating tumorigenesis [11]. These findings suggest that CRC-EVs modulate various changes in immune cells and mainly exhibit tumor-promoting effects. However, the underlying mechanisms by which CRC-EVs alter macrophage phagocytosis have not been fully elucidated.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC tissues [12]. Despite their phagocytic ability, macrophages cannot kill tumor cells due to the presence of “don't eat me” signals (such as CD47-SIRPα, PD1-PDL1, MHC I-LILRB1, and CD24-Siglec-10 signaling pathways) [13,14]. These “don't eat me” signals act as phagocytosis checkpoints that prevent macrophages from recognizing tumor antigens. In contrast, macrophages are involved in the phagocytosis of apoptotic tumor cells, which is also known as efferocytosis. During chemotherapy and radiotherapy, a large number of apoptotic tumor cells are generated, and lots of inflammatory factors are released to recruit macrophages [15]. Meanwhile, apoptotic tumor cells exhibit a series of “eat-me” signals such as phosphatidylserine and calreticulin, which are recognized by macrophage receptors [16]. The interaction between ligands and receptors mediates the engulfing of apoptotic cells and is defined as efferocytosis [17]. Efferocytosis reduces the release of inflammatory factors, prevents secondary necrosis, maintains the stability of the internal environment, and establishes a tumor-tolerant immunosuppressive environment [[18], [19], [20]]. The immunosuppressive role of macrophages in the phagocytosis of apoptotic tumor cells has been widely recognized. However, it is still unclear how TDEVs affect this process.

It is well known that heat shock protein 70 (HSP70) is expressed on the membranes of EVs and that large numbers of HSP70-positive EVs are released from breast, lung, and ovarian cancers [21]. HSP70 is a highly conserved and stress-induced molecular chaperone that facilitates protein folding/unfolding and transport across membranes [22]. The main function of HSP70 is to protect cells from different types of cellular stress, such as heat shock, oxidative stress, hypoxia, and altered pH [22,23]. In CRC, HSP70 is highly expressed and contributes to a poor prognosis, and HSP70 can promote tumor proliferation, migration, and invasion [24,25]. Moreover, extracellularly localized HSP70 acts as a carrier to deliver tumor-derived immunogenic peptides, which activate immune cells in the TME and elicit immune responses [26,27]. It has been reported that HSP70 binds to macrophage lipid raft microdomains, stimulating antigen phagocytosis, processing, and MHC-II presentation [28]. Currently, HSP70 is considered to be an important target for tumor therapy, and many inhibitors or vaccines targeting HSP70 have been developed and applied [29].

In this study, we demonstrated that CRC-EVs up-regulated the macrophage receptor with collagenous domains (MARCO), thereby promoting the phagocytic activity of macrophages. We further identified that CRC-EVs containing cargo protein HSP70 increased MARCO expression by activating the AKT-STAT3 signaling pathway. Our study revealed a novel EVs-mediated intercellular communication mechanism between CRC and macrophages, which has potential application in tumor therapy by targeting CRC-EV cargo proteins.

留言 (0)

沒有登入
gif