A comprehensive analysis of immune infiltration in the tumor microenvironment of osteosarcoma

Abstract

Background Even though immunotherapy has been an effective treatment for solid tumors, its efficacy in osteosarcoma remains sub‐optimal. It is therefore imperative to understand the complex tumor microenvironment (TME) of osteosarcoma to facilitate the development of immunotherapies against this cancer. Methods The mRNA expression profiles of osteosarcoma tissues were downloaded from The Cancer Genome Atlas (TCGA) database. Next, the ssGSEA, MCP‐counter, CIBERSORT, and Xcell algorithm analyses were performed to characterize the tumor microenvironment of osteosarcoma tissues. The tumor tissues were divided into inflammatory and non‐inflammatory. A comprehensive assessment of immune cell infiltration in osteosarcoma tissues was then performed. Sub‐group analysis of immune cell infiltration between men and women patients with osteosarcoma was also carried out. Results The results revealed that the infiltration of immune cells including activated B cell, activated CD8 T cell, CD56dim natural killer cell, and cytotoxic lymphocytes cells, in osteosarcoma tissues was higher in male than in female patients. Based on the infiltration profile of different immune cells, the osteosarcoma tissues were grouped into four clusters. The four clusters were further divided into hot and cold tumors. The differently expressed genes (DEGs) between cold and hot tumors were mainly associated with the activation and regulation of immune response. Additionally, a neuronal pentraxin (NPTX2) expression which was upregulated in cold tumors was found to be negatively correlated with the expression of CD8a Molecule (CD8A), Granzyme B (GZMB), and Interferon Gamma (IFNG). NPTX2 decreased CCL4 secretion. Knockdown of NPTX2 in osteosarcoma cells inhibited tumor growth and increased tumor cell apoptosis. Moreover, a prognosis prediction model of osteosarcoma was constructed and validated in patients receiving immunotherapy using external data. Conclusions To the best of our knowledge, this is the first study to characterize the infiltration of immune cells in osteosarcoma tissues from patients receiving immune infiltration therapy.

The role of SPI1-TYROBP-FCER1G network in oncogenesis and prognosis of osteosarcoma, and its association with immune infiltration

“…After recruiting immune cells into the tumor microenvironment by secreting CCL4 (collaborating with CCR5 to recruit CD8 + T cells, NK cells, monocytes, etc. [ 46 , 47 ]), CXCL10 (collaborating with CXCR3 to recruit CD8 + T cells, NK cells, etc. [ 48 – 50 ]), and CX3CL1 (not only collaborating with CX3CR1 to recruit CD4 + T cells, CD8 + T cells, dendritic cells [ 51 , 52 ], but also inducing OS metastasis via ICAM-1 [ 52 ]), molecules CD86 (co-stimulatory molecule CD86 polymorphism is also associated with increased susceptibility to osteosarcoma [ 53 ]) and MHCs (HLA-DPA1/HLA-DPB1/HLA-DRA) on the surfaces of the tumor cells, endothelial cells or DCs/macrophages can furtherly activated T cells in the microenvironment.…”

Expression of immune-related genes as prognostic biomarkers for the assessment of osteosarcoma clinical outcomes

“…Wu et al 21 found that the immune features indicated different immune infiltration levels of OS, and suggested immunotherapeutic opportunities in OS patients. CD8A functioned as key immune activation and cytotoxicity gene in OS, which provided insight into potential biomarkers of response and resistance in OS immunotherapies 27 , 30 . KIR2DL1 acted as an important NK cell inhibitory function, which provided an important insight into the mechanism of inhibitory immune checkpoints in future immunotherapies 31 .…”

Osteosarcoma in Children: Not Only Chemotherapy

“…Multiple clinical trials were needed to define this management strategy. The Multi-Institutional Osteosarcoma Study (MIOS) is one of the most significative clinical studies in demonstrating the superiority of surgery plus chemotherapy compared with surgery alone [27]. It lasted from 1982 to 1984 and highlighted an 11% 6-year survival rate for patients who received only surgery versus a 61% 6-year survival rate for those who received surgery plus adjuvant chemotherapy [27].…”

“…The Multi-Institutional Osteosarcoma Study (MIOS) is one of the most significative clinical studies in demonstrating the superiority of surgery plus chemotherapy compared with surgery alone [27]. It lasted from 1982 to 1984 and highlighted an 11% 6-year survival rate for patients who received only surgery versus a 61% 6-year survival rate for those who received surgery plus adjuvant chemotherapy [27]. In the same period at Memorial Sloan Kettering Cancer Center the neoadjuvant chemotherapy was introduced in the T10 protocol, in order to gain an extra time for the production of prosthetic devices and thus leading the increase of 5-years survival rate to 65% [28].…”

“…In the same period at Memorial Sloan Kettering Cancer Center the neoadjuvant chemotherapy was introduced in the T10 protocol, in order to gain an extra time for the production of prosthetic devices and thus leading the increase of 5-years survival rate to 65% [28]. Moreover, the Pediatric Oncology Group compared neoadjuvant and adjuvant chemotherapies in a randomized study, demonstrating that they have a similar outcome [27]. Since that moment, preoperative chemotherapy became the standard with all its related advantages: extra time to plan surgery, easier tumor removal, and increased number of the good responders [13].…”