ABSTRACT
BACKGROUND: Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and high mortality rate. In the search for effective therapeutic options, preclinical studies have suggested using systemic oxygenation to inhibit tumor growth and metastasis in various cancer models, including TNBC, by weakening the hypoxia-A2A adenosine receptors (A2AR)-driven immunosuppression in the tumor microenvironment (TME). In our present study, a hemoglobin-based oxygen carrier (HBOC) "YQ23" was tested for its role in modulating the TME and tumor inhibition. METHODS: A syngeneic TNBC mouse model was established by inoculating 4T1 cells subcutaneously in BALB/c mice. Tumor (~100 mm3) bearing mice were treated either with saline or YQ23 (400 mg/kg) i.v. once weekly. To prove the immune-regulatory role of YQ23, CD4+ and CD8+ cells were depleted from a group of mice prior to treatment. Tumor growth was monitored for four weeks while xenografts were isolated at the end of the treatment for ex vivo immunohistological examination. RESULTS: YQ23 significantly inhibited the tumor growth, and this suppressive effect was abolished by depleting the host immune cells. Immunohistochemical staining of xenograft sections showed YQ23 reduced the level of hypoxia and adenosine producing ecto-enzyme CD73. Although there was no significant difference in the make up of the intra-tumoral immune populations, we observed a down-regulation of the immune checkpoint PD-1. In concordance with the weakened immunosuppression, the inflammatory cytokine interferon γ and cytolytic granzyme B were upregulated. CONCLUSIONS: YQ23 treatment may be a potential therapeutic strategy to modulate the TME in TNBC.
ABSTRACT
OBJECTIVE: To examine whether the HIV-1 Tat protein impairs the lipopolysaccharide (LPS)-induced cytokine responses. DESIGN: Concurrent infections with pathogens including bacteria and viruses are common in AIDS patients. However, cytokine and interferon responses during infection with or translocation from the gut of these pathogens in HIV-infected patients are not well studied. As HIV-1 Tat contributes partly to the HIV-induced immune dysregulation, we investigated whether the protein may play a role in perturbing the LPS-induced cytokine responses. METHODS: Expression levels of cytokines in human primary blood monocytes/macrophages were determined by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Expression level of the cell surface Toll-like receptor 4 was examined by flow cytometry. Activations of signaling molecules were assayed by western blot and immunofluorescence. RESULTS: We demonstrated that HIV-1 Tat downregulated the LPS-induction of IFN-beta and concomitantly upregulated IL-6 expression in primary blood monocytes/macrophages, whereas the viral protein had no significant effects on TNF-alpha expression. To delineate the underlying mechanism, we showed that Tat inhibited the LPS-activation of ERK1/2 but not the p38 mitogen-activated protein kinases. The viral protein suppressed the LPS-induced activation of NFkappaB p65 via its induction of IkappaBalpha expression, which resulted in retention of NFkappaB p65 in the cytosol. CONCLUSION: These findings suggest that Tat may play a role in modulating the immune responses triggered by other coinfecting pathogens and thus providing a permissive environment for both HIV and other opportunistic microbes.
