Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 80 histological subtypes of STSs, data regarding novel biomarkers of strong prognostic and therapeutic value are very limited. To date, the most important prognostic factor is the tumor grade, and approximately 50% of patients that are diagnosed with high-grade STSs die of metastatic disease within five years. Systemic chemotherapy represents the mainstay of metastatic STSs treatment for decades but induces response in only 15-35% of the patients, irrespective of the histological subtype. In the era of immunotherapy, deciphering the immune cell signatures within the STSs tumors may discriminate immunotherapy responders from non-responders and different immunotherapeutic approaches could be combined based on the predominant cell subpopulations infiltrating the STS tumors. Furthermore, understanding the immune diversity of the STS tumor microenvironment (TME) in different histological subtypes may provide a rationale for stratifying patients according to the TME immune parameters. In this review, we introduce the most important immune cell types infiltrating the STSs tumors and discuss different immunotherapies, as well as promising clinical trials, that would target these immune cells to enhance the antitumor immune responses and improve the prognosis of metastatic STSs patients.

• Keywords
• IL-15, TILs, adoptive transfer, checkpoint inhibitors, immune cells, immunotherapy, sarcoma, trabectedin, tumor microenvironment,
• Publication type
• Journal Article MeSH
• Review MeSH

Salivary gland carcinomas (SGCs) are extremely morphologically heterogeneous, and treatment options for this disease are limited. Immunotherapy with immune checkpoint inhibitors (ICIs) represents a revolutionary treatment approach. However, SGCs remain largely resistant to this therapy. An increasing body of evidence suggests that resistance to ICI therapy is modulated by the Fas (CD95)-Fas ligand (FasL, CD178) interplay between tumor cells and immune cells. In this study, we examined the Fas-FasL interplay between tumor cells and tumor-infiltrating immune cells (TIICs) in the center and periphery of SGCs from 62 patients. We found that the Fas-expressing tumor cells accumulated in the center of SGC tumors with increasing tumor stage. Furthermore, this accumulation occurred regardless of the presence of TIICs expressing high levels of FasL. On the contrary, a loss of Fas-expressing TIICs with increasing tumor stage was found in the tumor periphery, whereas FasL expression in tumor cells in the tumor periphery correlated with tumor stage. These data suggest that SGC cells are resistant to FasL-induced apoptosis by TIICs but could utilize FasL to eliminate these cells in high-stage tumors to provide resistance to immunotherapy.

• Keywords
• Fas, FasL, salivary gland carcinoma, tumor center, tumor periphery,
• Publication type
• Journal Article MeSH

In a limited number of human malignancies, anti-CD47 therapy leads to the rapid clearance of tumor cells by macrophages. In esophageal squamous cell carcinoma, anti-CD47 treatment has shown promising results in vitro. However, the CD47 expression pattern in tumor-infiltrating lymphocytes (TILs), which are associated with prolonged overall survival and serve as a positive prognostic factor, is largely unknown. In this study, a total of 36 tissue samples from the tumor, peritumoral tissue, and adjacent healthy esophageal tissue was obtained from 12 esophageal carcinoma (EC) patients, and the surface expression of CD47 was evaluated in natural killer (NK) cells, CD8+ T cells, and the nonlymphocyte cell fraction. We found that the proportions of the evaluated cells and their CD47-expressing populations were comparable across the analyzed tissue compartments. However, the proportions of CD47-expressing populations in the analyzed tissue compartments were significantly higher in NK cells and CD8+ T cells than in the nonlymphocyte cell fraction. Importantly, the intensity of CD47 staining was also significantly higher in the tested immune cells than in the nonlymphocyte cell fraction. High expression of CD47 in tissue-infiltrating NK cells and CD8+ T cells in EC patients can, therefore, affect the efficacy of anti-CD47 therapy in EC.

• MeSH
• CD47 Antigen genetics   metabolism   MeSH
• Killer Cells, Natural metabolism   MeSH
• CD8-Positive T-Lymphocytes metabolism   MeSH
• Carcinoma metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Esophageal Neoplasms immunology   metabolism   MeSH
• Gene Expression Regulation, Neoplastic genetics   MeSH
• Aged MeSH
• Esophageal Squamous Cell Carcinoma MeSH
• Lymphocytes, Tumor-Infiltrating immunology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD47 Antigen MeSH
• CD47 protein, human MeSH Browser

PURPOSE: Esophageal cancer (EC) is one of the most lethal gastrointestinal malignancies. Immunotherapy is a promising treatment modality for this disease. However, broader implementation of EC immunotherapy has been discouraged because of insufficient understanding of tumor interactions with the immune system. As with other malignancies, the current research on EC focuses on deciphering the immune cell signatures within the tumor microenvironment. However, the disease-elicited immune cell profiles in the paratumoral compartments are largely unknown. METHODS: We examined the immune cell signatures in 62 tissue samples from 16 EC patients in different esophageal tissue compartments: tumor tissue, peritumoral tissue, healthy esophageal tissue, and adjacent lymph nodes. We analyzed the proportions and distribution patterns of NK cells and CD4+ and CD8+ T cells as well as their death receptor (FasR, FasR/DR3)-expressing subpopulations. The analyzed data were then compared and correlated with the patients' clinicopathological data. RESULTS: We found that the FasR+ NK cells, CD4+ and CD8+ T cells infiltrated lymph nodes at the lowest levels and that the FasR+DR3+ CD4+ T cells were enhanced in tumors. The comparisons with the clinicopathological data revealed a major impact of active smoking on the reduction in paratumoral NK cells and the upregulation of FasR in tumor-infiltrating NK and CD8+ T cells. The lymph node metastatic stage, tumor stage, and Mandard grade correlated with the compartmental proportions of the evaluated immune cells. CONCLUSION: The novel association of the disease state with tumoral and paratumoral immune cell signatures suggests new possibilities for personalized immunotherapy for EC patients.

• Keywords
• Death receptor 3, Esophageal cancer, Fas receptor, Mandard tumor regression grade, Peritumoral lymphocytes, Tumor-infiltrating lymphocytes,
• MeSH
• Adenocarcinoma immunology   pathology   therapy   MeSH
• fas Receptor immunology   MeSH
• Killer Cells, Natural immunology   pathology   MeSH
• CD4-Positive T-Lymphocytes immunology   pathology   MeSH
• CD8-Positive T-Lymphocytes immunology   pathology   MeSH
• Immunotherapy methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymph Nodes immunology   pathology   MeSH
• Lymphocytes immunology   pathology   MeSH
• Esophageal Neoplasms immunology   pathology   therapy   MeSH
• Aged MeSH
• Esophageal Squamous Cell Carcinoma immunology   pathology   therapy   MeSH
• Case-Control Studies MeSH
• T-Lymphocyte Subsets immunology   pathology   MeSH
• Lymphocytes, Tumor-Infiltrating immunology   pathology   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• fas Receptor MeSH