In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4068-4068
Abstract:
Cancers can aberrantly express carbohydrate antigens restricted to immature cells during prenatal human development, and these may be exploited for selective immune targeting. We studied expression and functional associations of the globo-series ganglioside stage-specific embryonic antigen 4 (SSEA4), a cell surface marker of human embryonic stem cells, in Ewing sarcoma (EwS). Flow cytometry revealed SSEA4 expression on the cell surface of each of 13 EwS cell lines, with moderate to high expression densities in 6 of 13 (46%) cell lines. Of 31 primary EwS tumor biopsies, 21 (68%) were SSEA4 positive by immunofluorescence staining. No associations of SSEA4 positivity with molecular or clinical disease parameters were found. Comparisons of paired tumor cell subpopulations with high and low/negative SSEA4 expression selected by cell sorting from 8 EwS cell lines revealed increased cell proliferation and colony formation of SSEA4high tumor cells, along with higher doxocrubicin chemoresistance and a higher propensity to migrate in transwell assays. SSEA4 negative cells selected from bulk populations of EwS cells regained SSEA4 expression during continued in vitro culture as well as after in vivo xenografting into immunodeficient mice. SSEA4high expression in EwS cells was not dependent on expression levels of the EWSR1-FLI1 fusion transcript or its direct targets, nor associated with markers of epithelial/mesenchymal plasticity. To retarget human T cells to SSEA4, we generated a second-generation, 41BBζ CAR using the antigen-binding domains of a murine anti-SSEA4 monoclonal antibody. SSEA4-specific CAR T cells specifically interacted with SSEA4 positive EwS cells in a strictly antigen-dependent manner, resulting in effective tumor cell lysis in vitro. We conclude that targeting of SSEA4 with CAR T cells or alternative immune therapeutics could be an attractive strategy to eliminate tumor cell subsets with high propensity to drive disease progression in EwS and therefore deserves further evaluation towards clinical translation. Citation Format: Silke Jamitzky, Bianca Altvater, Carolin Krekeler, Laura Hoen, Caroline Brandes, Lisa Richter, Julia Ebbinghaus, Laurin Ochs, Nicole Farwick, Katja Urban, Dennis Görlich, Ian Johnston, Rita Pfeifer, Claudia Rossig, Wolfgang Hartmann, Sareetha Kailayangiri. Ganglioside SSEA4 in Ewing sarcoma: A marker of tumor cells with highly aggressive features and a potential immune target. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4068.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-4068
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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