ABSTRACT
BACKGROUND: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS. METHODS: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro. RESULTS: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS. CONCLUSIONS: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.
Subject(s)
Anilides/pharmacology , Leiomyosarcoma/drug therapy , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Pyrazoles/pharmacology , Pyridines/pharmacology , Quinolines/pharmacology , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Apoptosis/drug effects , Blood Proteins/genetics , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Proliferation/genetics , Crizotinib , Disease-Free Survival , Female , G2 Phase Cell Cycle Checkpoints/drug effects , Gene Expression , Gene Silencing , Humans , Intercellular Signaling Peptides and Proteins/genetics , Leiomyosarcoma/genetics , Leiomyosarcoma/secondary , Male , Middle Aged , Phosphorylation/drug effects , Primary Cell Culture , Protein S , Tumor Stem Cell Assay , Young Adult , Axl Receptor Tyrosine KinaseSubject(s)
Liposarcoma/genetics , Liposarcoma/pathology , Nuclear Proteins/genetics , Proto-Oncogene Proteins/genetics , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathology , Aged , Cell Cycle Proteins , Gene Amplification , Humans , Male , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Proto-Oncogene Proteins c-mdm2/genetics , Shoulder/pathologyABSTRACT
Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade.
Subject(s)
Lung Neoplasms , Tertiary Lymphoid Structures , Antibodies, Monoclonal/therapeutic use , B7-H1 Antigen/therapeutic use , Humans , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Retrospective StudiesABSTRACT
Myopericytomas are exceedingly rare soft-tissue tumors with less than 10 cases including radiological depictions. We report three new cases of benign myopericytomas located in the soft-tissues of the hand in adult patients. A pre-treatment MRI was available for all patients and systematically evidenced well-defined, lobulated tumors closely related to the superficial palmar vascular arch and/or digital vessels with a perivascular pushing growth pattern that correlated with pathological findings. Though rare, this small case series show that myopericytomas display recurrent imaging features that could support their radiological diagnosis.