Immune dysregulation and osteosarcoma: Staphylococcus aureus downregulates TGF‐β and heightens the inflammatory signature in human and canine macrophages suppressed by osteosarcoma

Abstract

Since William Coley utilized bacterial immunotherapy to treat sarcomas in the late 19th century, an association between infection and improved survival has been reported for human and canine osteosarcoma patients. One of the reasons for this improved survival is likely a reactivation of the host immune system towards an inflammatory anti‐tumour response, and one of the key players is the macrophage. Yet, despite their importance, the response of macrophages to infectious agents in the context of osteosarcoma has not been thoroughly evaluated. The aim of this study was to evaluate how in vitro exposure to a bacterial agent (Staphylococcus aureus) influenced canine and human macrophage differentiation in the presence of osteosarcoma. Our hypothesis was that S. aureus would, in the presence of osteosarcoma, induce a macrophage phenotype with significantly increased inflammatory signatures. Consistent with our hypothesis, human macrophages co‐cultured with osteosarcoma and S. aureus exhibited increased IFN‐γ, TNF‐α and IL‐12p70 cytokine secretion, decreased TGF‐β cytokine secretion and increased mRNA expression of TNF‐α when compared with macrophages co‐cultured with osteosarcoma and to macrophages cultured alone. Canine macrophages similarly exhibited increased IFN‐γ and TNF‐α cytokine secretion, decreased TGF‐β cytokine secretion, increased mRNA expression of TNF‐α and increased surface receptor expression of CD80 when co‐cultured with osteosarcoma and S. aureus. Collectively, the findings of this study suggest that infection upregulates the inflammatory immune response to counteract osteosarcoma‐induced immune suppression. This work informs a potential therapeutic strategy to optimize inflammatory stimuli for triggering an anti‐osteosarcoma macrophage response.

Macrophages in Osteosarcoma Immune Microenvironment: Implications for Immunotherapy

“…Moreover, the depletion of macrophages reversed these anti-tumor responses ( 62 ). Besides, infection upregulates the cytokine secretion of inflammatory macrophages, including tumor necrosis factor-α (TNF-α) and interferon- γ (IFN- γ ), and reactivate the immune system towards anti-tumor response to attenuate immunosuppression induced by osteosarcoma ( 63 ). Although these models cannot precisely mimic the local inflammatory microenvironment of osteosarcoma, these preclinical researches, together with the above clinical data, provide a new understanding of the role of macrophages and the inflammatory response in osteosarcoma.…”

Development of a novel immune-related genes prognostic signature for osteosarcoma

“…However, they have not yet been used in clinical practice because of unavoidable limitations, such as overfitting due to small samples 12 . In recent decades, increasing evidence has indicated that the immune response is actively involved in OS occurrence and progression 13 . Immune genes act as pivotal regulator of immune response 14 , 15 .…”

“…They maintain the body's self-tolerance by strictly regulating the immune function and reducing the damage inflicted on the surrounding tissues 16 . However, OS cell may use these immune genes to escape the immune system and achieve a favorable environment for their growth 13 , 17 . Given the critical role of immune molecules in OS prognosis, these immune-related genes (IRGs) deserve further study.…”

Functional variant of IL33 is associated with survival of osteosarcoma patients

“…Collectively, it appeared that IL33 signaling could be associated with the immune response to tumorigenesis. Interestingly, impairment of antitumor immune response has been previously described for patients with OS [29]. Since the functional role of IL33 in the osteosarcomagenesis remains obscure, more experiments are warranted to unveil the underlying mechanism in the future study.…”