Increased CTLA-4+ T cells and an increased ratio of monocytes with loss of class II (CD14+ HLA-DRlo/neg) found in aggressive pediatric sarcoma patients

Abstract

BackgroundThere is little information regarding the composition of peripheral blood immunity in sarcoma patients and even less in the context of pediatric sarcomas. We describe the immune status using flow cytometry of peripheral blood in patients with osteosarcoma and Ewing sarcoma and demonstrate excessive CD14 in tumor tissues.MethodsPeripheral blood from patients with OS and ES was collected at diagnosis or relapse, and used for immune phenotyping of 74 different leukocyte phenotypes. Blood from young adult healthy volunteers was collected as controls. Tumor tissues were analyzed by immunohistochemistry.ResultsNineteen patients (average age = 14 y) and 16 controls (average age = 25y) were enrolled on study. Of the 74 phenotypes, 14 were different between sarcoma patients and HV. Sarcoma patients’ leukocytes contained a higher percentage of granulocytes (67 % sarcoma vs. 58 % HV; p = 0.003) and fewer lymphocytes (20 % sarcoma vs. 27 % HV; p = 0.001). Increased expression of CTLA-4 was seen in both T cells in sarcoma patients as compared to HV (p = 0.05). Increased CD14+ HLA-DRlo/neg immunosuppressive monocytes were seen in sarcoma patients (p = 0.03); primarily seen in OS. Increased tumor necrosis factor receptor II expression was seen on CD14+ cells derived from sarcoma patients as compared to HV (p = 0.01). Massive infiltration of CD14+ cells was seen in OS (>50 % of cells in the majority of tumors) compared to ES (<10-25 % of cells). In contrast, both OS and ES had limited T cell infiltration (generally <10 % of cells).ConclusionsPediatric sarcoma patients exhibit several immune phenotypic differences that were exacerbated in more severe disease. These phenotypes have the potential to contribute to immune suppression and may indicate potential targets for immune therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s40425-015-0082-0) contains supplementary material, which is available to authorized users.

Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

“…A peripheral blood monocyte count of >400 cells/μL has been significantly associated with decreased disease‐free interval in dogs with OSA . Others have reported associations between peripheral blood monocyte counts and outcomes in humans with OSA . Hence, we evaluated the flow cytometry data in conjunction with peripheral blood monocyte counts, using 400 cells/μL as a differentiation point between high and low monocyte counts according to previously reported findings .…”

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

“…The role of macrophages present in the vicinity of tumor cells, named "Tumor-Associated Macrophages" (TAMs), has been extensively studied [61][62][63]. [67]. Tim3/Gal9 interactions between T cells and myeloid cells could also result in an immunosuppressive response and repressed inflammation [68].…”

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…The key questions to answer in this context in OS include: What is known currently about the tumor immune profile? [74][75][76] Further, expression of PD-1 on tumor infiltrating lymphocytes and its ligand PD-L1 on tumor cells has been shown both in primary OS tumors as well as lung metastases, suggesting that this pathway might play a role in tumor microenvironment. Do OS primary and/or metastatic tumors have the right milieu for immune therapies to be effective?…”

“…Do OS primary and/or metastatic tumors have the right milieu for immune therapies to be effective? 75 Preclinical studies in immunocompetent mouse models suggest that blockade of immune checkpoint pathways alone or in combination with chemotherapy (trabectedin) or radiation can reduce both primary and metastatic tumor burden in bone and soft tissue sarcomas. What models can we use to study these questions?…”