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Updated: Jan 18, 2026
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Validation of a Seven-Gene Predictive SIGNature for the Efficacy of Immuno-Oncology PD-1 Inhibitors in Patients with
David S Moura1,2, Jesus Lopez-Marti1, Hussein Tawbi3
1Instituto de Investigacion Sanitaria Fundacion Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain.
Purpose:
Immune checkpoint inhibitors (ICI) have transformed cancer therapy, but their efficacy in sarcomas remains limited. A seven-gene predictive signature (CD86, CHI3L1, CXCL10, CXCL9, LAG3, NR4A1, and VCAM1) was previously identified as a biomarker for response to combined antiangiogenic and PD-1 inhibitor therapy in soft-tissue sarcomas. This study aimed to externally validate the predictive utility of this signature [SIGNature for immuno-oncology PD-1 inhibitors in sarcoma (SIGNIOS)] in an independent cohort of patients with sarcoma treated with ICIs.
Experimental Design:
Using RNA sequencing data from pretreatment tumor samples from the SARC028 phase II trial (pembrolizumab for advanced sarcomas) and the GEIS-32 phase II trial (pazopanib in advanced solitary fibrous tumor), we calculated the SIGNIOS score. Patients were stratified into low (score 0-4) and high (score 5-7) risk groups.
Results:
The SARC028 validation cohort comprised 31 patients, with a median age of 33 years, and 45.2% were female. The most common histologic subtypes included osteosarcoma (25.8%) and Ewing sarcoma (19.4%). The seven-gene signature significantly stratified patients into groups with significantly different progression-free survival (PFS): Those with scores of 0 to 4 had a median PFS of 49 days, whereas those with scores of 5 to 7 had a median PFS of 170 days [HR = 0.71 (95% confidence interval, 0.55-0.91), P = 0.007].
Conclusions:
This external validation confirms the seven-gene signature as a potential biomarker for predicting ICI efficacy in advanced sarcomas. Prospective studies are needed to determine the prognostic versus predictive value of SIGNIOS, refine its use across sarcoma subtypes, and explore its applicability in other tumor types.
Insights
A seven-gene signature (SIGNIOS) effectively predicts immune checkpoint inhibitor (ICI) response in advanced sarcomas. This validation confirms its potential as a biomarker for improving sarcoma treatment outcomes.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Discovery
Background:
- Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but show limited efficacy in sarcomas.
- A previously identified seven-gene signature (SIGNIOS) showed promise for predicting response to combined anti-angiogenic and PD-1 inhibitor therapy in soft-tissue sarcomas (STS).
Purpose of the Study:
- To externally validate the predictive utility of the SIGNIOS seven-gene signature in an independent cohort of sarcoma patients treated with ICIs.
- To assess the SIGNIOS signature's ability to stratify patients based on predicted response to immunotherapy.
Main Methods:
- RNA-Seq data from pre-treatment tumor samples from the SARC028 and GEIS-32 phase 2 trials were analyzed.
- The SIGNIOS score was calculated, and patients were stratified into low (0-4) and high (5-7) risk groups.
- Progression-free survival (PFS) was compared between the low- and high-risk groups.
Main Results:
- The validation cohort included 31 patients with advanced sarcomas, including osteosarcoma and Ewing sarcoma.
- The SIGNIOS signature significantly stratified patients by PFS.
- Patients with high SIGNIOS scores (5-7) had a significantly longer median PFS (170 days) compared to those with low scores (0-4) (49 days) [HR=0.71, p=0.007].
Conclusions:
- External validation confirms the seven-gene SIGNIOS signature as a potential predictive biomarker for ICI efficacy in advanced sarcomas.
- Further prospective studies are required to establish the prognostic versus predictive value of SIGNIOS.
- Refining SIGNIOS for specific sarcoma subtypes and exploring its utility in other cancer types are warranted.
