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Augmentation of natural killer ( NK ) cell cytotoxicity is one of the greatest challenges for cancer immunotherapy. Although histidine‐rich glycoprotein ( HRG ), a 75‐ kD a glycoprotein with various immunomodulatory activities, reportedly elicits antitumor immunity, its effect on NK cell cytotoxicity is unclear. We assessed NK cell cytotoxicity against K562 cells. We also measured concentrations of cytokines and granzyme B in the cell supernatant. The proportion of CD 56 bright NK cells and NK cell surface PD ‐1 expression was assessed with flow cytometry. The neutralizing effects of anti‐C‐type lectin‐like receptor ( CLEC ) 1B against HRG were also measured. NK cell morphological changes were analyzed via confocal microscopy. HRG significantly increased NK cell cytotoxicity against K562 cell lines. HRG also increased the release of granzyme B and the proportion of CD 56 bright NK cells. Further, HRG was able to decrease NK cell surface PD ‐1 expression. The effects of HRG on NK cells were reversed with anti‐ CLEC ‐1B antibodies. Additionally, we confirmed NK cell nuclear morphology and F‐actin distribution, which are involved in the regulation of cytotoxic granule secretion. Because both PD ‐1 and CLEC ‐1B are associated with prognosis during malignancy, HRG incorporates these molecules to exert the antitumor immunity role. These facts indicate the potential of HRG to be a new target for cancer immunotherapy.
Augmentation of natural killer ( NK ) cell cytotoxicity is one of the greatest challenges for cancer immunotherapy. Although histidine‐rich glycoprotein ( HRG ), a 75‐ kD a glycoprotein with various immunomodulatory activities, reportedly elicits antitumor immunity, its effect on NK cell cytotoxicity is unclear. We assessed NK cell cytotoxicity against K562 cells. We also measured concentrations of cytokines and granzyme B in the cell supernatant. The proportion of CD 56 bright NK cells and NK cell surface PD ‐1 expression was assessed with flow cytometry. The neutralizing effects of anti‐C‐type lectin‐like receptor ( CLEC ) 1B against HRG were also measured. NK cell morphological changes were analyzed via confocal microscopy. HRG significantly increased NK cell cytotoxicity against K562 cell lines. HRG also increased the release of granzyme B and the proportion of CD 56 bright NK cells. Further, HRG was able to decrease NK cell surface PD ‐1 expression. The effects of HRG on NK cells were reversed with anti‐ CLEC ‐1B antibodies. Additionally, we confirmed NK cell nuclear morphology and F‐actin distribution, which are involved in the regulation of cytotoxic granule secretion. Because both PD ‐1 and CLEC ‐1B are associated with prognosis during malignancy, HRG incorporates these molecules to exert the antitumor immunity role. These facts indicate the potential of HRG to be a new target for cancer immunotherapy.
Tissue Factor (TF) is the initiator of blood coagulation but also functions as a signal transduction receptor. TF expression in breast cancer is associated with higher tumor grade, metastasis and poor survival. The role of TF signaling on the early phases of metastasis has never been addressed. Here, we show an association between TF expression and metastasis as well as cancer stemness in 574 breast cancer patients. In preclinical models, blockade of TF signaling inhibited metastasis tenfold independent of primary tumor growth. TF blockade caused a reduction in epithelial-to-mesenchymal-transition, cancer stemness and expression of the pro-metastatic markers Slug and SOX9 in several breast cancer cell lines and in ex vivo cultured tumor cells. Mechanistically, TF forms a complex with β1-integrin leading to inactivation of β1-integrin. Inhibition of TF signaling induces a shift in TF-binding from α3β1-integrin to α6β4 and dictates FAK recruitment, leading to reduced epithelial-to-mesenchymal-transition and tumor cell differentiation. In conclusion, TF signaling inhibition leads to reduced pro-metastatic transcriptional programs, and a subsequent integrin β1 and β4-dependent reduction in metastasic dissemination.
Prostate cancer (PC) has previously been established as a cold tumor and develops in an inert immunosuppressive environment. Current research focuses on altering the immune microenvironment of PC from cold to hot; thus, in the present review, the diverse roles of estrogen and estrogen receptor (ER) signaling was examined in the tumor cell and tumor immune microenvironment (TIM). We hypothesized that ERα promotes PC progression and ERβ impedes epithelial-mesenchymal transition in PC cells, while in the TIM, ERβ mediates the immunosuppressive environment, and low levels of ERα is associated with disease development. Selective estrogen receptor modulators (SERMs) or selective ER degraders play diverse roles in the regulation of ER isoforms. Patients with PC may benefit from the use of SERMs, including raloxifene, in combination with anti-PD1/PD-L1 checkpoint immunotherapy, or TGF-β or Wnt antagonists. The present review demonstrated that immunotherapy-based strategies combined with SERMs may be an option for the future of PC-targeting therapy.
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