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Observational Study
. 2024 Oct 23;17(1):100.
doi: 10.1186/s13045-024-01614-w.

Predictive value of tumor microenvironment on pathologic response to neoadjuvant chemotherapy in patients with undifferentiated pleomorphic sarcomas

Jean Philippe Guegan  1 , Nathan El Ghazzi  2   3 , Julien Vibert  4 , Christophe Rey  1 , Lucile Vanhersecke  5 , Jean Michel Coindre  5 , Maud Toulmonde  2 , Mariella Spalato Ceruso  2 , Florent Peyraud  2 , Alban Bessede  1 , Antoine Italiano  6   7
Affiliations
Observational Study

Predictive value of tumor microenvironment on pathologic response to neoadjuvant chemotherapy in patients with undifferentiated pleomorphic sarcomas

Jean Philippe Guegan et al. J Hematol Oncol. .

Abstract

Undifferentiated pleomorphic sarcomas (UPS) represent a prevalent and aggressive subtype of soft tissue sarcomas (STS) in adults. Despite advancements in loco regional treatments, many patients with high grade STS, including UPS, develop metastatic disease. Neoadjuvant chemotherapy is a standard approach to mitigate this risk, but response variability necessitates refined patient selection strategies. This study investigated the correlation between UPS microenvironment and neoadjuvant chemotherapy response in resectable UPS. The NEOSARCOMICS study (NCT02789384) enrolled patients with resectable STS from six sarcoma centers in France. Patients received anthracycline based chemotherapy, followed by surgery. Histological response, gene expression profiling, and multiplex immunohistofluorescence were performed on baseline and post treatment tumor samples. Plasma proteomics was analyzed to identify biomarkers. Good responders to neoadjuvant chemotherapy showed enrichment in genes related to stemness and cell cycle regulation, while poor responders exhibited immune related gene enrichment. Proteomic profiling revealed immune pathway activation and downregulation of cell cycle pathways in non responders. Despite being associated with a good prognosis, high immune infiltration, particularly of CD8 + T cells and CD20 + B cells, predicts a poor response to neoadjuvant chemotherapy in UPS, suggesting the need for alternative therapeutic strategies for patients with inflamed UPS.Ongoing clinical trials are exploring the efficacy of combining chemotherapy with immune checkpoint inhibitors to improve outcomes.

Keywords: Soft tissue sarcoma.

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Conflict of interest statement

AB and JPG: Employees of Immusmol/Explicyte. AI: Received research grants from Astra Zeneca, Bayer, BMS, Chugai, Merck, MSD, Pharmamar, Novartis, Roche, and received personal fees from BMS, MSD, Merck, Roche, Epizyme, Bayer, Lilly, Roche, and Springworks. The other authors have nothing to disclose.

Figures

Fig. 1
Fig. 1
Response to neoadjuvant chemotherapy correlates with high proliferation and low immune infiltration phenotype. (A) Workflow of RNAseq experiment performed on baseline tumor samples from UPS patients treated with neoadjuvant chemotherapy. (B) Volcano plot representation of genes differentially expressed between responder (R) and non responder (NR) patients. (C) Heatmap visualization of Gene Ontology biological process enrichment scores. (D) Boxplot representation of immune cells estimation (CIBERSORT) according to response to neoadjuvant chemotherapy. P values were calculated using Wilcoxon tests
Fig. 2
Fig. 2
Poor response to neoadjuvant chemotherapy is associated with baseline immune infiltrates in UPS patients. (A) Workflow of multiplex IHF validation experiment (left). Representative images of tumor FFPE section of non responder (NR) and responder (R) patients stained with the multiplex panel CD8 / CD14 / CD20 / CD45 / CD68 / cMAF / DAPI. (B) Heatmap visualization of cell densities of indicated immune cell populations in UPS patients. (C) Boxplot representation of CD8 + cell densities according to percentage of tumors cell at surgery. P values were calculated using Wilcoxon tests. (D) Workflow of plasma proteomic analysis using Olink Explore 3072. (E) Volcano plot representation of protein differentially secreted at baseline between CD8 + high and low UPS patients. (F) Bubble plot of Gene Ontology terms enrichment
See this image and copyright information in PMC

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