68MO - Multi-omics profiling identifies two epithelioid sarcoma molecular subtypes with distinct signaling and immune characteristics

Background

Epithelioid sarcoma (EpS) is an aggressive malignancy characterized by SMARCB1 loss and traditionally classified as “distal” or “proximal” according to clinicopathological features. EpS molecular characteristics remain largely unknown.Therapeutically, the enhancer of zeste homolog 2 (EZH2) small molecule inhibitor, tazemetostat, was recently approved by the Food and Drug Administration for the treatment of advanced EpS. It was the first ever approved epigenetic drug for solid tumors, making the proof-of-concept of the utility of targeting epigenetic regulation in epigenetically-driven solid cancers. However, only 15% of EpS responded to tazemetostat, supporting that some inter- and/or intra-patient heterogeneity may determine sensitivity to treatment. In this context, a molecular classification, which would not only allow to better understand EpS pathogenicity and diversity, but also help orient therapeutic decision making, is crucially lacking.

Methods

To establish an EpS molecular classification and uncover molecular determinants of EpS heterogeneity, we used multi-omics profiling and integrated the genomic, transcriptional and methylome landscapes with single-cell and spatial transcriptomics.

Results

We identify two EpS molecular subtypes distinct from the clinicopathological ones, which we called” distal-like” and “proximal-like”. “Distal-like” tumors harbor a cancer cell-specific epithelial-to-mesenchymal transition signature associated with improved patient survival and Desmoglein 2 expression as a diagnostic biomarker; they also exhibit higher peri-tumoral CD8+ T-cell infiltrates with specific tumor-immune interactions. Proximal-like EpS display a higher inter-tumoral heterogeneity, increased intra-tumoral immunosuppressive macrophages, and some similarities with other SMARCB1-deficient tumors.

Conclusions

Our study introduces an EpS molecular classification that extends beyond traditional clinicopathological one and paves the way for precision medicine-based therapeutic strategies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

S. Postel-Vinay.

Funding

This work was funded by program grants to SPV from INSERM ATIP-Avenir / La Ligue Contre le Cancer 2018; Fondation ARC (PGA1-RF20190208576), European Research Council ERC (TargetSWitch 101077864), Cancéropôle Ile-de-France (2017-1-EMERG-72 and 2020-1-EMRG-28-IGR-1), La Ligue contre le Cancer Val de Marne (Subvention Recherche Scientifique 2021 et 2022), and Agence Nationale pour la Recherche (RHU Condor ANR-21-RHUS-0010). This work was further funded by program grants to Gustave Roussy from Institut National du Cancer (INCa-DGOS-Inserm_12551 SIRIC2 and INCa-DGOS-Inserm-ITMO Cancer_18002 SIRIC EpiCURE), as well as the “Program Epigenetique Emergent” funded by The Fondation Gustave Roussy.

Disclosure

S. Postel-Vinay: Other, Institutional, Principal Investigator, clinical trial: Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharma; Other, Institutional, Advisory Board: Merck KGaA; Financial Interests, Personal, Funding: AMGEN and Hoffman LaRoche. All other authors have declared no conflicts of interest.