Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature. Issue 1 (10th January 2022)

• Record Type: Journal Article
• Authors: Bertucci, Francois; Niziers, Vincent; de Nonneville, Alexandre; Finetti, Pascal; Mescam, Léna; Mir, Olivier; Italiano, Antoine; Le Cesne, Axel; Blay, Jean-Yves; Ceccarelli, Michele; Bedognetti, Davide; Birnbaum, Daniel; Mamessier, Emilie
• Is Part Of: Journal for immunotherapy of cancer. Volume 10:Issue 1(2022)
• Publication Date: 2022-01-10
• Subjects: gene expression profiling -- sarcoma; Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2021-003687
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: Soft-tissue sarcomas (STSs) are heterogeneous and aggressive tumors, with high metastatic risk. The immunologic constant of rejection (ICR) 20-gene signature is a signature of cytotoxic immune response. We hypothesized that ICR might improve the prognostic assessment of early-stage STS. Methods: We retrospectively applied ICR to 1455 non-metastatic STS and searched for correlations between ICR classes and clinicopathological and biological variables, including metastasis-free survival (MFS). Results: Thirty-four per cent of tumors were classified as ICR1, 27% ICR2, 24% ICR3, and 15% ICR4. These classes were associated with patients' age, pathological type, and tumor depth, and an enrichment from ICR1 to ICR4 of quantitative/qualitative scores of immune response. ICR1 class was associated with a 59% increased risk of metastatic relapse when compared with ICR2-4 class. In multivariate analysis, ICR classification remained associated with MFS, as well as pathological type and Complexity Index in Sarcomas (CINSARC) classification, suggesting independent prognostic value. A prognostic clinicogenomic model, including the three variables, was built in a learning set (n=339) and validated in an independent set (n=339), showing greater prognostic precision than each variable alone or in doublet. Finally, connectivity mapping analysis identified drug classes potentially able to reverse the expression profile of poor-prognosis tumors, such as chemotherapy and targeted therapies. Conclusion: ICR signature is independently associated with postoperative MFS in early-stage STS, independently from other prognostic features, including CINSARC. We built a robust prognostic clinicogenomic model integrating ICR, CINSARC, and pathological type, and suggested differential vulnerability of each prognostic group to different systemic therapies.