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-tumo...

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Bibliographic Details
Published in:	Cells (Basel, Switzerland) Vol. 10; no. 11; p. 3070
Main Authors:	Biele, Emilie, Schober, Sebastian J, Prexler, Carolin, Thiede, Melanie, Heyking, Kristina von, Gassmann, Hendrik, Eck, Jennifer, Xue, Busheng, Burdach, Stefan, Thiel, Uwe
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 08-11-2021 MDPI
Subjects:	Antigens Antigens, CD CD83 CD83 Antigen Cell Line, Tumor Cell surface Cell therapy CHM1319-specific TCR-transgenic T cells Cytokines Cytotoxicity Dendritic cells Dendritic Cells - metabolism Dendritic Cells - pathology Ewing sarcoma Flow cytometry Gene expression Gene Expression Regulation, Neoplastic Herpes viruses Histocompatibility antigen HLA Histocompatibility Antigens Class I - metabolism Humans Hyperthermia Immunogenicity Immunoglobulins Immunotherapy Inflammation Intercellular adhesion molecule 1 Intercellular Adhesion Molecule-1 - metabolism Interleukin 6 Lymphocytes Lymphocytes T Macrophages Major histocompatibility complex Maturation Membrane Glycoproteins Metastases Monocytes Monocytes - pathology Patients Pediatrics Prostaglandin E2 R&D Research & development Sarcoma Sarcoma, Ewing - genetics Sarcoma, Ewing - immunology Software Solid tumors Surface markers T cell receptors T-Lymphocytes, Cytotoxic - immunology Tumor cells Tumor necrosis factor Tumor Necrosis Factor-alpha - metabolism Tumor-infiltrating lymphocytes Up-Regulation - genetics United States > US CHM1319-specific TCR-transgenic T cells Ewing sarcoma CD83 immunotherapy
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Summary:	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. However, new adjuvant techniques to induce long lasting and curative CHM1 -specific TCR-transgenic T cell-mediated anti-tumor responses are needed. In this work, we sought to identify a technique to improve the cytotoxic effect of CHM1 -specific TCR-transgenic T cell by altering the immunogenic cell surface marker expression on EwS cell lines using different cytokines. We demonstrate that TNF, IL-6, IL-1β and PGE cause pro-immunogenic CD83, MHC class I and II as well as ICAM-1 upregulation in EwS cell lines. This observation was associated with significantly improved recognition and killing of the tumor cells by EwS-specific CHM1 /HLA-A*02:01-restricted TCR-transgenic T cells. Conclusively, we demonstrate that the induction of an inflammatory signature renders EwS more susceptible to adoptive T cell therapy. TNF, which is upregulated during inflammatory processes, is of particular translational interest as its secretion may be induced in the patients e.g., by irradiation and hyperthermia in the clinical setting. In future clinical protocols, this finding may be important to identify appropriate conditioning regimens as well as point of time for adoptive T cell-based immunotherapy in EwS patients.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2073-4409 2073-4409
DOI:	10.3390/cells10113070