Conditional activation of immune-related signatures and prognostic significance: a pan-cancer analysis

Roelands, Jessica; Hendrickx, Wouter; Kuppen, Peter J.K.; Mall, Raghvendra; Zoppoli, Gabriele; Saad, Mohamad; Halliwill, Kyle; Curigliano, Giuseppe; Rinchai, Darawan; Decock, Julie; Delogu, Lucia Gemma; Turan, Tolga; Samayoa, Josue; Chouchane, Lotfi; Wang, Ena; Finetti, Pascal; Bertucci, François; Miller, Lance D.; Galon, Jérôme; Marincola, Francesco M.; Ceccarelli, Michele; Bedognetti, Davide

doi:10.1101/546069

Cited by 5 publications

(3 citation statements)

References 49 publications

(72 reference statements)

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“…A higher mutation burden in cancer has been associated with an increased abundance of neoantigens, which can elicit immune responses and potentially lead to favorable responses to immunotherapy in types of cancer (Tran et al, 2017;Roelands et al, 2020;Huang et al, 2021). Our results showed that MUC4, AHNAK2, AHNAK, FLG2, MUC5AC, MUC3A, and MUC17 were the most common alterations in PGs.…”

Section: Discussionmentioning

confidence: 61%

Identification and validation of a novel HOX-related classifier signature for predicting prognosis and immune microenvironment in pediatric gliomas

Jiao

Zhang

et al. 2023

Front. Cell Dev. Biol.

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Background: Pediatric gliomas (PGs) are highly aggressive and predominantly occur in young children. In pediatric gliomas, abnormal expression of Homeobox (HOX) family genes (HFGs) has been observed and is associated with the development and progression of the disease. Studies have found that overexpression or underexpression of certain HOX genes is linked to the occurrence and prognosis of gliomas. This aberrant expression may contribute to the dysregulation of important pathological processes such as cell proliferation, differentiation, and metastasis. This study aimed to propose a novel HOX-related signature to predict patients’ prognosis and immune infiltrate characteristics in PGs.Methods: The data of PGs obtained from publicly available databases were utilized to reveal the relationship among abnormal expression of HOX family genes (HFGs), prognosis, tumor immune infiltration, clinical features, and genomic features in PGs. The HFGs were utilized to identify heterogeneous subtypes using consensus clustering. Then random forest-supervised classification algorithm and nearest shrunken centroid algorithm were performed to develop a prognostic signature in the training set. Finally, the signature was validated in an internal testing set and an external independent cohort.Results: Firstly, we identified HFGs significantly differentially expressed in PGs compared to normal tissues. The individuals with PGs were then divided into two heterogeneous subtypes (HOX-SI and HOX-SII) based on HFGs expression profiles. HOX-SII showed higher total mutation counts, lower immune infiltration, and worse prognosis than HOX-SI. Then, we constructed a HOX-related gene signature (including HOXA6, HOXC4, HOXC5, HOXC6, and HOXA-AS3) based on the cluster for subtype prediction utilizing random forest supervised classification and nearest shrunken centroid algorithm. The signature was revealed to be an independent prognostic factor for patients with PGs by multivariable Cox regression analysis.Conclusion: Our study provides a novel method for the prognosis classification of PGs. The findings also suggest that the HOX-related signature is a new biomarker for the diagnosis and prognosis of patients with PGs, allowing for more accurate survival prediction.

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Section: Discussionmentioning

confidence: 61%

Identification and validation of a novel HOX-related classifier signature for predicting prognosis and immune microenvironment in pediatric gliomas

Jiao

Zhang

et al. 2023

Front. Cell Dev. Biol.

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“…The cancer survival analysis with TCGA data was performed using UCSC XENA (https://xena.ucsc.edu) and for that with the gene expression array data was performed using KM plotter (http://kmplot.com) (34). Correlation between CCL5 and markers of stemness (cancer stem cells and normal stem cells) and epithelial to mesenchymal transition (EMT) markers, was performed by using a normalized RNA matrix, described elsewhere (35). The selection of markers was based on current literature (36).…”

Section: In Silico Analysis Of Ccl5 Gene Expressionmentioning

confidence: 99%

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

et al. 2019

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Triple-negative breast cancer (TNBC) accounts for ∼15-20% of breast cancer (BC) and has a higher rate of early relapse and mortality compared to other subtypes. The Chemokine (C-C motif) ligand 5 (CCL5) and its signaling pathway have been linked to TNBC. We aimed to investigate the susceptibility and prognostic implications of genetic variation in CCL5 signaling genes in TNBC in the present study. We characterized variants in CCL5 and that of six other CCL5 signaling genes (CCND1, ZMIZ1, CASP8, NOTCH2, MAP3K21, and HS6ST3) among 1,082 unrelated Tunisian subjects (544 BC patients, including 196 TNBC, and 538 healthy controls), assessed the association of the variants with BC-specific overall survival (OVS) and progression-free survival (PFS), and correlated CCL5 mRNA and serum levels with CCL5 genotypes. We found a highly significant association between the CCND1 rs614367-TT genotype (OR = 5.14; P = 0.004) and TNBC risk, and identified a significant association between the rs614367-T allele and decreased PFS in TNBC. A decreased risk of lymph node metastasis was associated with the MAP3K21 rs1294255-C allele, particularly in rs1294255-GC (OR = 0.47; P = 0.001). CCL5 variants (rs2107538 and rs2280789) were linked to CCL5 serum and mRNA levels. In the TCGA TNBC/Basal-like cohort the MAP3K21 rs1294255-G allele was associated with a decreased OVS. High expression of CCL5 in breast tumors was significantly associated with an increased OVS in all BC patients, but particularly in TNBC/Basal-like patients. In conclusion, genetic variation in CCL5 signaling genes may predict not only TNBC risk but also disease aggressiveness.

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“…These tumor-type-specific differences might be due to differences in the underlying oncogenic dysregulations. For instance, we recently demonstrated that the prognostic value of Th1 immune infiltration is dependent on the activation status of specific oncogenic processes such as proliferation and TGF-B signaling, even within the same cancer type (Bertucci et al 2018;Roelands et al 2019).…”

Section: Introductionmentioning

confidence: 99%

The Immune landscape of pediatric solid tumors

Sherif¹,

Roelands²,

Mifsud³

et al. 2021

Preprint

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BackgroundImmunotherapy is quickly coming to the forefront of cancer treatment; however, the implementation of immunotherapy in solid pediatric cancers, which classically display a low mutational load, is hindered by insufficient understanding of the determinants of cancer immune responsiveness in children. In order to better understand tumor-host interplay, we sought to characterize solid pediatric cancers based on immunological parameters using analytes extracted from gene expression data.MethodsWe used RNAseq data from the publicly available TARGET studies for five pediatric solid tumor types (408 patients): Wilms tumor (WT), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of previously identified immune signatures like the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response associated with favorable prognosis and responsiveness to immunotherapy. We also performed gene set enrichment analysis (ssGSEA) and clustering, using more than 100 immune signatures to define immune subtypes in pediatric tumors and compared the overall survival across subtypes. The expression of immune checkpoints and enrichment of oncogenic pathways were also assessed across the immune subtypes.ResultsThe five tumor types showed distinct ICR score distributions. A higher ICR score was associated with better survival in OS and NBL-HR-MYCN_NA, but with poorer survival in WT. The clustering of immune signatures revealed the same five principal modules observed in adult solid tumors: Wound Healing, TGF-B signaling, IFN-G signaling, Macrophages, and Lymphocytes. These modules clustered pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival and was characterized by low enrichment of the wound healing signature, high Th1, low Th2. Conversely, cluster S4 showed the worst survival and highest enrichment of wound healing signature, low Th1, and high Th2. Furthermore, the upregulation of the WNT/Beta-catenin pathway is associated with unfavorable outcomes and lack of T-cell infiltration in OS.ConclusionsWe demonstrated that extracranial solid pediatric tumors could be classified according to their immune disposition, unveiling similarity 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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Conditional activation of immune-related signatures and prognostic significance: a pan-cancer analysis

Cited by 5 publications

References 49 publications

Identification and validation of a novel HOX-related classifier signature for predicting prognosis and immune microenvironment in pediatric gliomas

Identification and validation of a novel HOX-related classifier signature for predicting prognosis and immune microenvironment in pediatric gliomas

Genetic Variation in CCL5 Signaling Genes and Triple Negative Breast Cancer: Susceptibility and Prognosis Implications

The Immune landscape of pediatric solid tumors

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