Cytokine screening identifies TNF to potentially enhance immunogenicity of pediatric sarcomas.

Introduction: Pediatric sarcomas, including osteosarcoma (OS), Ewing sarcoma (EwS) and rhabdomyosarcoma (RMS) carry low somatic mutational burden and low MHC-I expression, posing a challenge for T cell therapies. Our previous study showed that mediators of monocyte maturation sensitized the EwS cell line A673 to lysis by HLA-A*02:01/CHM1-specific allorestricted T cell receptor (TCR) transgenic CD8 T cells (CHM1 CD8 T cells).

Methods: In this study, we tested a panel of monocyte maturation cytokines for their ability to upregulate immunogenic cell surface markers on OS, EwS and RMS cell lines, using flow cytometry.

TCR-transgenic T cells and YB-1-based oncolytic virotherapy improve survival in a preclinical Ewing sarcoma xenograft mouse model.

Background: Ewing sarcoma (EwS) is an aggressive and highly metastatic bone and soft tissue tumor in pediatric patients and young adults. Cure rates are low when patients present with metastatic or relapsed disease. Therefore, innovative therapy approaches are urgently needed.

Correlation of Transcriptomics and FDG-PET SUVmax Indicates Reciprocal Expression of Stemness-Related Transcription Factor and Neuropeptide Signaling Pathways in Glucose Metabolism of Ewing Sarcoma.

Background: In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as prognostic factors. However, the biological basis for the generally elevated but variable glucose metabolism in EwS is not well understood.

No Improvement of Survival for Alveolar Rhabdomyosarcoma Patients After HLA-Matched Versus -Mismatched Allogeneic Hematopoietic Stem Cell Transplantation Compared to Standard-of-Care Therapy.

Background: Patients with stage IV alveolar rhabdomyosarcoma (RMA) have a 5-year-survival rate not exceeding 30%. Here, we assess the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for these patients in comparison to standard-of-care regimens. We also compare the use of HLA-mismatched vs.

Monocyte Maturation Mediators Upregulate CD83, ICAM-1 and MHC Class 1 Expression on Ewing's Sarcoma, Enhancing T Cell Cytotoxicity.

Ewing's sarcoma (EwS) is a pediatric solid tumor entity with low somatic mutational burden and a low rate of tumor-infiltrating T cells, indicating a low extent of immunogenicity. In EwS, immunogenicity may furthermore be significantly diminished by a predominantly M2 macrophage driven pro-tumorigenic tumor microenvironment. In the past, we demonstrated that CHM1-specific TCR-transgenic T cells are able to control EwS growth in a preclinical mouse model as well as in a patient with metastatic disease.

Class I histone deacetylases (HDAC) critically contribute to Ewing sarcoma pathogenesis.

Background: Histone acetylation and deacetylation seem processes involved in the pathogenesis of Ewing sarcoma (EwS). Here histone deacetylases (HDAC) class I were investigated.

Methods: Their role was determined using different inhibitors including TSA, Romidepsin, Entinostat and PCI-34051 as well as CRISPR/Cas9 class I HDAC knockouts and HDAC RNAi.

MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress.

Cancer cells are in most instances characterized by rapid proliferation and uncontrolled cell division. Hence, they must adapt to proliferation-induced metabolic stress through intrinsic or acquired antimetabolic stress responses to maintain homeostasis and survival. One mechanism to achieve this is reprogramming gene expression in a metabolism-dependent manner.

MHC Class I-Restricted TCR-Transgenic CD4 T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo.

In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4 versus CD8 T cells targeting a peptide from (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4 T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide.

Combined Inhibition of Epigenetic Readers and Transcription Initiation Targets the EWS-ETS Transcriptional Program in Ewing Sarcoma.

Background: Previously, we used inhibitors blocking BET bromodomain binding proteins (BRDs) in Ewing sarcoma (EwS) and observed that long term treatment resulted in the development of resistance. Here, we analyze the possible interaction of BRD4 with cyclin-dependent kinase (CDK) 9.

Methods: Co-immunoprecipitation experiments (CoIP) to characterize BRD4 interaction and functional consequences of inhibiting transcriptional elongation were assessed using drugs targeting of BRD4 or CDK9, either alone or in combination.

Transcriptome based individualized therapy of refractory pediatric sarcomas: feasibility, tolerability and efficacy.

Survival rates of pediatric sarcoma patients stagnated during the last two decades, especially in adolescents and young adults (AYAs). Targeted therapies offer new options in refractory cases. Gene expression profiling provides a robust method to characterize the transcriptome of each patient's tumor and guide the choice of therapy.