A potential novel therapeutic target for invasive soft tissue sarcoma detected through tumor immune microenvironment and genetic profile analyses.
Authors: Ariga Akane , Funauchi Yuki , Kobayashi Yukari , Nagaoka Koji , Sato Yasuyoshi , Sato Shingo , Yoshii Toshitaka , Ae Keisuke , Takahashi Shunji , Kakimi Kazuhiro 
Published: June 2024

11550

Background: Improvements in surgical techniques and the introduction of perioperative chemotherapy have led to the improved 5-year survival rate of 91% for bone and tissue sarcoma in Japan (JCOG1306 trial). However, for invasive soft tissue sarcomas, the local control rate remains approximately 80% with a high recurrence rate. Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) frequently exhibit strong local invasiveness, yet the mechanisms underlying their invasiveness remain unclear. Thus, in this study, we aimed to explore the tumor microenvironment and genetic profiles associated with the invasiveness of UPS and MFS by using bulk RNA-sequencing data. Methods: We focused on 47 cases with UPS or MFS, whose RNA-sequencing data were obtained from surgical specimens at the Cancer Institute Hospital of JFCR between April 2017 and April 2023. The entire cohort was divided into two groups based on preoperative MRIs. Tumors showing a tail-like sign or irregular margins were categorized as invasive (Group I: 32 cases, average age 71±13 years, UPS 22 cases, MFS 10 cases), while tumors with clearly defined margins were categorized as non-invasive (Group NI: 15 cases, average age 68±13 years, UPS 10 cases, MFS 5 cases). We calculated immune cell fractions using CIBERSORTx and analyzed the differentially expressed genes (DEGs) and altered pathways using iDEP estimated from RNA-sequencing data. The results were analyzed for correlation with clinical outcomes. Results: The 5-year overall survival rate was significantly lower in Group I (74%) than in Group NI (100%, p=0.04), while the 5-year recurrence-free survival rate did not differ significantly between the groups (p=0.4). Group I showed significantly lower naive B cell count (p=0.04), and cases with higher naive B cell count had a significantly higher 5-year overall survival rate than those with lower count (93% vs. 69%, p=0.04). A total of 1260 DEGs were identified between Group I and NI, including 241 immune-related genes, and 11 genes were associated with overall survival. Multivariate analysis of these 11 immune-related genes and overall survival revealed the significant association of one gene, “Gene X” (p=0.01). In Group I, pathways related to fat metabolism were downregulated, while those related to sugar metabolism and rheumatoid arthritis were upregulated. Conclusions: This study revealed that soft tissue sarcoma invasiveness is correlated with overall survival. Specific tumor-infiltrating immune cells and immune-related genes may be regulated by the associated metabolic pathways. The pathways including “Gene X”, which reported with its antibodies, may contribute to the regulation of invasiveness of invasive soft tissue sarcoma and the improvement in survival rate. Thus, “Gene X” may be considered a potential novel therapeutic target for invasive soft tissue sarcoma.