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PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas
François Bertucci1, Pascal Finetti2, Delphine Perrot3
1Department of Molecular Oncology, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, UMR1068 Inserm, Marseille, France; Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France; Aix-Marseille University, Marseille, France; French Sarcoma Group, Lyon, France.
Abstract:
Soft-tissue sarcomas (STS) are a group of rare, heterogeneous, and aggressive tumors, with high metastatic risk and relatively few efficient systemic therapies. In the quest for new treatments, the immune system represents an attractive therapeutic target. Recently, PD1/PDL1 inhibitors showed very promising results in patients with solid tumors. PDL1 expression has been rarely studied in STS, in small series only, by using immunohistochemistry (IHC), and with non-concordant prognostic implications. Here, we have analyzed PDL1 mRNA expression in 758 clinical STS samples retrospectively profiled using DNA microarrays and RNAseq, and searched for correlations with clinicopathological variables including metastasis-free survival (MFS) after surgery. PDL1 expression was heterogeneous across the samples. PDL1-high samples (41%) were more frequently leiomyosarcomas and liposarcomas, and showed more frequently a complex genetic profile and a high-risk CINSARC signature. No correlation existed with other clinicopathological features such as tumor site, depth, and pathological tumor grade and size. In multivariate prognostic analysis, the PDL1-high class was associated with shorter MFS, independently of the pathological type and the CINSARC signature. Analysis of correlations with biological factors suggested the existence in tumors of the PDL1-high class of a strong and efficient cytotoxic T-cell response, however associated with some degree of T-cell exhaustion and negative regulation. In conclusion, we show that PDL1 expression refines the prediction of metastatic relapse in operated localized STS, and that PD1/PDL1 blockade holds potential to improve patient survival by reactivating inhibited T cells to increase the antitumor immune in PDL1-high tumors.
Insights
High programmed death-ligand 1 (PDL1) expression in soft-tissue sarcomas (STS) predicts shorter metastasis-free survival. PD1/PDL1 blockade may improve survival in PDL1-high STS by enhancing antitumor immunity.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Soft-tissue sarcomas (STS) are rare, aggressive tumors with limited treatment options.
- Immune checkpoint inhibitors targeting PD1/PDL1 show promise in solid tumors.
- PDL1 expression and its prognostic role in STS are poorly understood.
Purpose of the Study:
- To analyze PDL1 mRNA expression in a large cohort of STS.
- To correlate PDL1 expression with clinicopathological variables and metastasis-free survival (MFS).
- To explore the potential of PD1/PDL1 blockade in STS treatment.
Main Methods:
- Retrospective analysis of PDL1 mRNA expression in 758 STS samples using DNA microarrays and RNAseq.
- Correlation analysis with clinicopathological features and MFS.
- Multivariate prognostic analysis.
Main Results:
- PDL1 expression was heterogeneous, with 41% of samples classified as PDL1-high.
- PDL1-high tumors were more frequent in leiomyosarcomas and liposarcomas, often showing complex genetic profiles and high-risk CINSARC signatures.
- PDL1-high expression was independently associated with shorter MFS.
- Analysis suggested an efficient but exhausted cytotoxic T-cell response in PDL1-high tumors.
Conclusions:
- PDL1 expression refines metastatic relapse prediction in operated localized STS.
- PD1/PDL1 blockade therapy holds potential for improving survival in PDL1-high STS by reactivating T cells and boosting antitumor immunity.