High throughput profiling of undifferentiated pleomorphic sarcomas identifies two main subgroups with distinct immune profile, clinical outcome and sensitivity to targeted therapies

Abstract

Background Undifferentiated pleomorphic sarcoma (UPS) is the most frequent, aggressive and less-characterized sarcoma subtype. This study aims to assess UPS molecular characteristics and identify specific therapeutic targets. Methods High-throughput technologies encompassing immunohistochemistry, RNA-sequencing, whole exome-sequencing, mass spectrometry, as well as radiomics were used to characterize three independent cohorts of 110, 25 and 41 UPS selected after histological review performed by an expert pathologist. Correlations were made with clinical outcome. Cell lines and xenografts were derived from human samples for functional experiments. Findings CD8 positive cell density was independently associated with metastatic behavior and prognosis. RNA-sequencing identified two main groups: the group A, enriched in genes involved in development and stemness, including FGFR2, and the group B, strongly enriched in genes involved in immunity. Immune infiltrate patterns on tumor samples were highly predictive of gene expression classification, leading to call the group B ‘ immune-high’ and the group A ‘ immune-low’. This molecular classification and its prognostic impact were confirmed on an independent cohort of UPS from TCGA. Copy numbers alterations were significantly more frequent in immune-low UPS. Proteomic analysis identified two main proteomic groups that highly correlated with the two main transcriptomic groups. A set of nine radiomic features from conventional MRI sequences provided the basis for a radiomics signature that could select immune-high UPS on their pre-therapeutic imaging. Finally, in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 was selectively shown in cell lines and patient-derived xenograft models derived from immune-low UPS. Interpretation Two main disease entities of UPS, with distinct immune phenotypes, prognosis, molecular features and MRI textures, as well as differential sensitivity to specific anticancer agents were identified. Immune-high UPS may be the best candidates for immune checkpoint inhibitors, whereas this study provides rational for assessing FGFR inhibition in immune-low UPS. Funding This work was partly founded by a grant from La Ligue.

Proteomic profiling of soft tissue sarcomas with SWATH mass spectrometry

“…In UPS, our data finds that this subgroup is enriched in gene sets associated with leukocyte activation. This result is consistent with a very recent transcriptomic study which showed that UPS can been classified into two distinct molecular subgroups, one of which is characterised by genes involved in inflammatory response and immune cell signatures [ 9 ]. The enrichment of an immune cell proteomic signature in UPS, where immune checkpoint inhibitors have showed some clinical activity [ 26 , 27 ], suggests that future inclusion of proteomic profiling in cancer immunotherapy trials may lead to new predictive biomarkers that complement currently available approaches [ 40 ].…”

“…However, this study utilised the reverse phase protein array (RPPA) platform which is limited to the analysis of 192 proteins/phosphoproteins. Other studies that utilise mass spectrometry (MS) have largely been limited to 1–2 subtypes including recent proteomic analyses of gastrointestinal stromal tumours (GIST) and undifferentiated pleomorphic sarcomas (UPS) which identified distinct clinical and molecular subgroups [ 6 , 8 , 9 ]. To date few MS-based analysis has been conducted across multiple histological subtypes in STS.…”

Fibroblast Growth Factor Receptor (FGFR) Signaling in GIST and Soft Tissue Sarcomas

“…Additionally, Toulmonde et al recently used a multi-omics platform to characterize UPS and identified a subgroup of UPS characterized by low expression of markers of immune activation. This subgroup showed an enrichment in genes involved in development and stemness including in particular FGFR2 , which they propose to potentially represent a therapeutic target [ 49 ]. Similarly, FGFR1 and FGFR2 transcripts are enriched in subtype I of LMS, a transcriptionally defined molecular subtype characterized by the overexpression of genes involved in muscle contraction, muscle system processes, and cytoskeleton organization [ 50 ].…”

“…In FGFR2-overexpressing myxoid liposarcoma cell lines, the FGFR TKIs PD173074, dovitinib and infigratinib, reduced cell proliferation and migration, and this effect was further increased by their combination with the standard chemotherapeutic agent trabectedin [ 41 ]. Recently, the FGFR TKIs erdafitinib, infigratinib, and AZD4547 have been shown to decrease in vitro viability, FGFR2 phosphorylation, and downstream signaling, and induced G0–G1 arrest in cells derived from immune-low UPS, which are characterized by the overexpression of FGFR2 [ 49 ]. Finally, pharmacological FGFR inhibition significantly impaired the growth of patient-derived xenografts from immune-low UPS, but had no effect on those from immune-high UPS [ 49 ].…”

“…Recently, the FGFR TKIs erdafitinib, infigratinib, and AZD4547 have been shown to decrease in vitro viability, FGFR2 phosphorylation, and downstream signaling, and induced G0–G1 arrest in cells derived from immune-low UPS, which are characterized by the overexpression of FGFR2 [ 49 ]. Finally, pharmacological FGFR inhibition significantly impaired the growth of patient-derived xenografts from immune-low UPS, but had no effect on those from immune-high UPS [ 49 ]. Similarly, the TKIs ponatinib, dovitinib, infigratinib, and PD173074 have been tested in preclinical models of Ewing sarcoma, where they have shown the capability to suppress cellular proliferation [ 56 , 57 ].…”