Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature

Bertucci, François; Niziers, Vincent; Nonneville, Alexandre de; Finetti, Pascal; Mescam, Léna; Mir, Olivier; Italiano, Antoîne; Cesne, Axel Le; Blay, Jean‐Yves; Ceccarelli, Michele; Bedognetti, Davide; Birnbaum, Daniel; Mamessier, Émilie

doi:10.1136/jitc-2021-003687

Cited by 19 publications

(21 citation statements)

References 69 publications

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“…The ICR has been associated with better prognosis in the breast cancer [ 33 , 34 ], in which it could further stratify high-risk patients defined by standard prognostic signatures used in the clinical practice [ 35 ]. Added prognostic value has also been observed in a large meta-analysis of gene expression data from patients with sarcoma [ 36 ]. Moreover, ICR modules have been associated with response to checkpoint inhibitions and other forms of immunotherapy, including adoptive therapy [ 37 ], vaccine therapy [ 38 ], and local immunotherapy (Imiquimod) [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

The immune landscape of solid pediatric tumors

Sherif

Roelands

Mifsud

et al. 2022

J Exp Clin Cancer Res

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Background Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart. Methods We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome. Results A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS. Conclusions We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults’ tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.

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Section: Introductionmentioning

confidence: 99%

The immune landscape of solid pediatric tumors

Sherif

Roelands

Mifsud

et al. 2022

J Exp Clin Cancer Res

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“…The pre-analytic processing of data was done as previously described [ 11 ]. Briefly, a first step of normalization was applied to each data set separately, by using quantile normalization for the already processed non-Affymetrix data, and Robust Multichip Average (RMA) with non-parametric quantile algorithm for the raw Affymetrix data.…”

Section: Methodsmentioning

confidence: 99%

“…The first one is the improvement of prognostic factors that will help to better define the role, if any, of adjuvant chemotherapy. Historically associated with pathological grade [ 8 ] and size, and depth [ 9 ], the prognostic characterization is being refined, thanks to the contribution of genomic signatures such as CINSARC [ 10 ] or the immunologic constant of rejection (ICR) signature [ 11 ]. Clinical trials assessing prospectively the clinical utility of CINSARC (NCT03805022, NCT04307277) are ongoing.…”

Section: Introductionmentioning

confidence: 99%

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CSPG4 expression in soft tissue sarcomas is associated with poor prognosis and low cytotoxic immune response

et al. 2022

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Background Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. Methods We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. Results CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients’ age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42–57) 5-year DFS versus 61% (95% CI 56–68) in patients with low expression (p = 3.17E−03), representing a 49% increased risk of event in the “CSPG4-high” group (HR = 1.49, 95% CI 1.14–1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between “CSPG4-high” and “CSPG4-low” tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. Conclusions Patients with “CSPG4-high” STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, “CSPG4-low” STS are better candidates for immune therapy involving ICI.

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“…Here, we identified immune-related lncRNA signatures (and proxy protein-coding gene network) that are associated with clinical outcome and immune checkpoint expression in breast cancer and have prognostic value in multiple cancer types. Using the large TCGA breast cancer dataset, we first identified differentially expressed immune-related lncRNAs (ir-lncRNAs) in immune favorable versus immune unfavorable tumors as defined by the Immunologic Constant of Rejection (ICR), a prognostic gene signature of tumor immune activation [26][27][28][29][30]. Next, we mapped the ir-lncRNAs to a codingnon-coding gene network enabling the identification of proximal protein-coding genes using the random walk with restart (RWR) computational algorithm.…”

Section: Introductionmentioning

confidence: 99%

Immune-related 3-lncRNA signature with prognostic connotation in a multi-cancer setting

et al. 2022

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Background Advances in our understanding of the tumor microenvironment have radically changed the cancer field, highlighting the emerging need for biomarkers of an active, favorable tumor immune phenotype to aid treatment stratification and clinical prognostication. Numerous immune-related gene signatures have been defined; however, their prognostic value is often limited to one or few cancer types. Moreover, the area of non-coding RNA as biomarkers remains largely unexplored although their number and biological roles are rapidly expanding. Methods We developed a multi-step process to identify immune-related long non-coding RNA signatures with prognostic connotation in multiple TCGA solid cancer datasets. Results Using the breast cancer dataset as a discovery cohort we found 2988 differentially expressed lncRNAs between immune favorable and unfavorable tumors, as defined by the immunologic constant of rejection (ICR) gene signature. Mapping of the lncRNAs to a coding-non-coding network identified 127 proxy protein-coding genes that are enriched in immune-related diseases and functions. Next, we defined two distinct 20-lncRNA prognostic signatures that show a stronger effect on overall survival than the ICR signature in multiple solid cancers. Furthermore, we found a 3 lncRNA signature that demonstrated prognostic significance across 5 solid cancer types with a stronger association with clinical outcome than ICR. Moreover, this 3 lncRNA signature showed additional prognostic significance in uterine corpus endometrial carcinoma and cervical squamous cell carcinoma and endocervical adenocarcinoma as compared to ICR. Conclusion We identified an immune-related 3-lncRNA signature with prognostic connotation in multiple solid cancer types which performed equally well and in some cases better than the 20-gene ICR signature, indicating that it could be used as a minimal informative signature for clinical implementation.

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Immunologic constant of rejection signature is prognostic in soft-tissue sarcoma and refines the CINSARC signature

Cited by 19 publications

References 69 publications

The immune landscape of solid pediatric tumors

The immune landscape of solid pediatric tumors

CSPG4 expression in soft tissue sarcomas is associated with poor prognosis and low cytotoxic immune response

Immune-related 3-lncRNA signature with prognostic connotation in a multi-cancer setting

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