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  • br cells Fig A C indicating a novel

    2020-08-30


    cells DMAPP (Fig. 6A–C), indicating a novel immune escape mechanism for the CD90hi population. To further verify our hypothesis, CD4+ and CD8+ T DMAPP isolated from human PBMCs were cultured together with CD90hi and CD90− SW1990 cells, respectively. T cell proliferation was assessed by CFSE dilution. Compared with CD90− cells, CD90hi PDAC cells have a stronger inhibitory effect on T cell proliferation (both CD4+ and CD8+) (Fig. 6D). Moreover, a positive relationship between THY1 (CD90) and CD247 (PD-L1) mRNA levels was observed in TCGA (PAAD) database (Fig. 6E). Hence, the above results demonstrated the mole-cular mechanism by which CD90 mediated the crosstalk between pancreatic CSCs and surrounding monocytes/macrophages and T cells, which created an immunosuppressive microenvironment for PDAC progression (Fig. 6F).
    4. Discussion
    Cancer stem cells (CSCs) play an important role in the development and progression of pancreatic cancer. CSCs reside in niches, specialized microenvironments that protect them from the immune system and could enhance their stemness and metastatic potential [38,39]. The identification of pancreatic CSCs remains challenging. The investigation of CSCs and specialized microenvironments in which they thrive might provide novel therapeutic targets for pancreatic cancer. In our current study, we aimed to identify “stem-like” cells in pancreatic cancer and to investigate how these cells communicate with adjacent immune cells.
    CD90 is a marker of mouse and human hematopoietic stem cells and has been described as a tumor-initiating cell marker in multiple solid tumors [16–20]. Previous reports have found that CD90 is expressed on stromal cells in PDAC tissues; however, its expression on PDAC cells has not yet been defined [21,22]. Here, using a pancreatic cancer tissue array from Renji Hospital, we confirmed that CD90 could be expressed on both stromal and tumor cells in PDAC. PDAC cell lines and primary cells were used to further confirm its expression on PDAC cells. To further understand how CD90 is involved in PDAC progression, GSEA was performed on the CD90hi and CD90low groups according to CD90 expression in PDAC patients. In line with the function of CD90 in other tumors, CD90hi PDAC samples showed a significant enrichment of genes upregulated in mammary stem cells. Moreover, by using a panel of stemness-related experiments, we further confirmed that the CD90hi population in PDAC harbored stemness properties with higher ALDH activity, sphere formation capability and tumorigenicity compared to CD90− cells. Given that CD90 is a plasma membrane receptor without an intracellular domain, it is unlikely to be a determinant for the stemness of PDAC cells. Instead, “stem-like cells” highly express CD90, which might be a strategy for them to enhance communication with surrounding cells.
    The immunosuppressive microenvironment is a common feature in most solid tumors. Generally, the host immune system serves as a barrier against tumor formation. However, after transformation, im-mune cells are often redirected by tumor cells into an im-munosuppressive state. This strategy is more necessary for CSCs to evade immune surveillance and sustain their stemness state. Recent years have seen immense progress in our understanding of how tumors interface with immune cells; however, few studies have shed light on how CSCs interact with immune cells in a manner different from non-CSCs. Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are responsible for immunosuppressive and tumor-promoting activity. CD90 is a GPI-anchored glycoprotein that interacts with integrins displayed by adjacent cells, such as the surface marker CD11b/MAC-1 (integrin alpha M/beta), which is expressed on monocytes/macrophages [31]. CD90, which is expressed on breast cancer stem cells, was shown to mediate the physical interaction be-tween CSCs and macrophages and is one mechanism by which CSCs maintain their “stem-like” state. Here, in our current study, we found that CD90hi PDAC cells could tether and reprogram monocytes/mac-rophages into an immunosuppressive state; in turn, these monocytes/  Cancer Letters 453 (2019) 158–169
    macrophages served to sustain the stemness/EMT features of PDAC cells. In addition to mediating physical interactions, very little is known about CD90 signaling capabilities. CD90 lacks an intracellular domain and hence is unable to transduce signals alone. Here, we found that CD90 acts as an anchor to enhance the communication between CD90hi PDAC cells and monocytes/macrophages in a near-secretory manner. However, other possibilities require further study, including whether CD90 could transactivate other receptors for signal transduction and whether the expression of CD90 on pancreatic stromal cells also med-iates the crosstalk between monocytes/macrophages and stromal cells.