Dataset Information

Tumor immunogenomic signatures improve a prognostic model of melanoma survival.

ABSTRACT:

Background

Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT.

Methods

Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two validation cohorts Cox PH models assessed the interaction between TMB and 53 melanoma immunogenomic features to refine prediction of melanoma OS.

Results

Interferon-? response (IFN?Res) and macrophage regulation gene signatures (MacReg) combined with TMB significantly associated with OS (p?=?8.80E-14). We observed that patients with high TMB, high IFN?Res and high MacReg had significantly better OS compared to high TMB, low IFN?Res and low MacReg (HR?=?2.8, p?=?3.55E-08). This association was not observed in low TMB patients.

Conclusions

We report a model combining TMB and tumor immune features that significantly improves prediction of melanoma OS, independent of IT. Our analysis revealed that patients with high TMB, high levels of IFN?Res and MacReg had significantly more favorable OS compared to high TMB patients with low IFN?Res and low MacReg. These findings may substantially improve current melanoma prognostic models.

SUBMITTER: Morales L

PROVIDER: S-EPMC7888085 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Tumor immunogenomic signatures improve a prognostic model of melanoma survival.

Morales Leah L Simpson Danny D Ferguson Robert R Cadley John J Esteva Eduardo E Monson Kelsey K Chat Vylyny V Martinez Carlos C Weber Jeffrey J Osman Iman I Kirchhoff Tomas T

Journal of translational medicine 20210217 1

<h4>Background</h4>Tumor mutation burden (TMB) has been associated with melanoma immunotherapy (IT) outcomes, including survival. We explored whether combining TMB with immunogenomic signatures recently identified by The Cancer Genome Atlas (TCGA) can refine melanoma prognostic models of overall survival (OS) in patients not treated by IT.<h4>Methods</h4>Cox proportional-hazards (Cox PH) analysis was performed on 278 metastatic melanomas from TCGA not treated by IT. In a discovery and two valida ...[more]

PMID: 33596955

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Project description:Tumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion. A defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis. Patients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of MYCN amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of MYCN, ASCL1, SOX11, and KMT2A transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts. Our results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions.

Dataset Information

Tumor immunogenomic signatures improve a prognostic model of melanoma survival.

Background

Methods

Results

Conclusions

Publications

Tumor immunogenomic signatures improve a prognostic model of melanoma survival.

Similar Datasets

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