Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions

Lezot

2019

Cellular Immunology

171

183

Section: Lymphocytes Subpopulations In Osteosarcoma and Therapeutic Imentioning

confidence: 85%

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

Lezot

2019

Cellular Immunology

171

183

“…In osteosarcoma, PD-L1 staining was evaluated by immunofluorescence (monoclonal antibody from Abcam), indicating PD-L1 expression in 75% of metastatic lesions but not on primary tumors. 41 Heterogeneity not only between sarcoma subtypes but also within tumors is another issue to take into consideration. Thus evaluation of PD-L1 expression within each histological subtype seems more relevant to estimate the prevalence and predictive value of this immune marker.…”

Section: Discussionmentioning

confidence: 99%

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

et al. 2016

Therapies targeting the programmed cell death 1 (PD-1) or its ligand (PD-L1) promote antitumor T-cell activity, leading to unprecedented long-lasting tumor responses in some advanced cancers. Because of radiotherapy and chemotherapy resistance, no effective treatments have been defined for advanced chondrosarcomas. We here report an immunohistochemical analysis of PD-L1 expression in a large series of conventional, mesenchymal, clear cell and dedifferentiated chondrosarcomas using tissue microarrays. In the PD-L1-positive tumors, we analyzed the immune microenvironment (T-cell and macrophage infiltration as well as HLA class I expression) using whole sections. PD-L1 expression was absent in conventional (n = 119), mesenchymal (n = 19) and clear cell (n = 20) chondrosarcomas. Forty-one percent (9 of the 22) of dedifferentiated chondrosarcomas displayed PD-L1 positivity. These results were confirmed in an independent cohort using whole tissue sections of dedifferentiated chondrosarcomas in which PD-L1 expression was detected in 52% (11 of the 21) of cases. PD-L1 expression was exclusively found in the dedifferentiated component and expression positively correlated with other immune parameters such as high number of tumor-infiltrating lymphocytes (P = 0.014) and positive HLA class I expression (P = 0.024) but not with patient overall survival (P = 0. Chondrosarcomas constitute a malignant group of cartilaginous matrix-producing neoplasms, with diverse morphological features and clinical behavior. 1 Conventional chondrosarcoma is the second most common primary bone malignancy after osteosarcoma and can be categorized according to their location into central (85%) and peripheral chondrosarcomas (15%). Their histology is similar, with atypical chondrocytes and abundant extracellular matrix, but they differ at the genetic level. Notably, mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in approximately half of conventional central chondrosarcomas while mutations in genes encoding exostosin (EXT) 1 and 2 characterize peripheral chondrosarcomas. 2,3 Histological grade is strongly correlated with clinical prognosis with a 10-year survival rate of 83% for atypical cartilaginous tumor/grade I but only 29% for grade III. In addition to conventional chondrosarcoma, several rare subtypes of chondrosarcoma are discerned (dedifferentiated, mesenchymal and clear cell), together constituting 10-15% of all chondrosarcomas. Clear cell chondrosarcoma is a low-grade malignant tumor with a 10-year survival rate reported around 90% while dedifferentiated and mesenchymal chondrosarcoma are both highly malignant, with frequent occurrence of distant metastases and o30% survival at 5 and 10 years, respectively. 4

“…2,87 Monoclonal antibodies targeting immune checkpoint mechanisms show remarkable efficiency in several types of malignancy and are also evaluated in OS preclinical models and clinical trials. 2,[88][89][90] Nevertheless, even with novel therapeutic targets, drug resistance is an emerging aspect of inefficient OS treatment. Combination regimens are being continuously designed in order to overcome acquired resistance to chemotherapy.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Deciphering signaling networks in osteosarcoma pathobiology

Adamopoulos

Gargalionis

Basdra

et al. 2016

Exp Biol Med (Maywood)

Osteosarcoma is the most frequent type of primary bone tumors among children and adolescents. During the past years, little progress has been made regarding prognosis of osteosarcoma patients, especially for those with metastatic disease. Genomic instability and gene alterations are common, but current data do not reveal a consistent and repeatable pattern of osteosarcoma development, thus paralleling the tumor's high heterogeneity. Critical signal transduction pathways have been implicated in osteosarcoma pathobiology and are being evaluated as therapeutic targets, including receptor activator for nuclear factor-kB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction pathways. Herein, we recapitulate and discuss recent advances in the context of molecular mechanisms and signaling networks that contribute to osteosarcoma progression and metastasis, towards patient-tailored and novel-targeted treatments.