Osteosarcoma (OS) is a highly malignant stromal tumor composed of mesenchymal cells that produce osteoid and immature bone. The peak of incidence is in the second decade after birth. Although relatively rare, the social impact of this type of tumor is particularly relevant. In contrast to cancer, the role of Molecular genetics of Osteosarcoma progression and its special Tumor microenvironment (TME) – bone – remains largely unknown.
Although TME has been widely studied in other solid tumors to describe its role in tumor progression and some in a distant spread, research on tumor interstitial interactions in OS has been quite neglected for decades, partly due to the rarity of OS tumors, the specific site of OS occurrence in the bone, and the lack of syngeneic mouse models, allowing for the involvement of innate and acquired immune cells.
However, due to recent technological advances in Transcriptome, Proteomics, and Bioinformatics, researchers have gained a new wave of knowledge about OS TME.
Recently, researchers from the National Cancer Institute of the IRCCS Foundation published an article on J Exp Clin Cancer Res entitled “Rewiring innate and adaptive immunity with TLR9 agonist to treat osteosarcoma”. This research data shows that TLR9 agonist plays the role of in situ anti-tumor vaccine and activates the innate immune response sufficient to inhibit local tumor growth, simultaneously, selective amplification of CD8T cell clones is required to induce systemic adaptive immunity, and CD8T cell clones are necessary for non-local effects.
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Surgery and multi-drug chemotherapy are the standards of treatment, and at the time of diagnosis, the event-free survival rate of local diseases reaches 60% -70%. However, for metastatic diseases, the prognosis is discouraging. Utilizing immune system activation in the context of this unfavorable mesenchymal tumor poses a new therapeutic challenge.
In an immune active OS mouse model with two contralateral lesions, we tested the efficacy of TLR9 agonists on both treated and untreated contralateral lesions to evaluate nonendoscopic effects. Multi-parameter flow cytometry was used to detect changes in the tumor immune microenvironment. In the experiment of immune-deficient mice, the role of adaptive T cells in the TLR9 agonist effect can be studied, and T-cell receptor sequencing can be used to evaluate the expansion of specific T cell clones.
The TLR9 agonist has a strong inhibitory effect on the growth of locally treated tumors, and its therapeutic effect extends to untreated tumors on the opposite side. Multi-parameter flow cytometry showed that after TLR9 binding, the immune pattern of the OS immune microenvironment underwent significant changes, including a decrease in M2-like macrophages and an increase in infiltration of dendritic cells and activated CD8T cells in both lesions.
It is worth noting that CD8T cells are necessary to induce abnormal effects, but they are not strictly necessary conditions to prevent the growth of lesions after treatment. The T-cell receptor (TCR) sequencing of tumor-infiltrating CD8T cells showed that specific TCR clones expanded in the treated tumors. It is worth noting that their selective expression in the untreated lesions on the opposite side provided the first evidence for the reconnection of tumor-related T cell clone structures.
In conclusion, the work of this study proves the anti-tumor activity of TLR9 in OS, which is a high-level and invasive tumor, and no targeted therapy or effective immunotherapy is available. The evidence provided by this study suggests that reprogramming the tumor immune microenvironment may be a valuable way to improve the effectiveness of standards or new treatment methods in cold tumor types with poor invasiveness (such as OS).
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Reference
Caterina Cascini et al. Rewiring innate and adaptive immunity with TLR9 agonist to treat osteosarcoma. J Exp Clin Cancer Res. 2023 Jun 26;42(1):154. doi: 10.1186/s13046-023-02731-z.