An Evaluation of the Tumor Microenvironment through CALR, IL1R1, IFNB1, and IFNG to Assess Prognosis and Immunotherapy Response in Bladder Cancer Patients
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eLife assessment
This study investigates the associations of four ICD-related genes in bladder cancer with increased immune cell infiltration and more prolonged survival. The study is valuable because it identifies a risk-scoring model, showing a correlation between high-risk scores based on four ICD-related genes and weak anti-tumour immune function. However, the evidence supporting the association of these genes and immunotherapy response is incomplete.
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Abstract
Immunogenic cell death (ICD) is a type of cell death sparking adaptive immune responses, can reshape the tumor microenvironment (TME). Exploring key ICD-related genes in bladder cancer (BLCA) could enhance personalized treatment. TCGA BLCA patients were divided into two ICD subtypes: ICD-high and ICD-low. High ICD expression linked to increased immune cell infiltration and longer survival, but with potentially suppressed immune function. The high ICD group responded better to PD1-targeted therapy. A risk-scoring model with four ICD-related genes (CALR, IL1R1, IFNB1, IFNG) was validated across TCGA, GEO datasets, and tissue samples, showing higher risk-score correlated with weaker anti-tumor immune function, more tumor-promoting elements, lower immunotherapy response rates, and shorter patient survival.This study connects ICD-related genes to BLCA prognosis and immune infiltration, offering a vital tool for personalized treatment guidance.
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eLife assessment
This study investigates the associations of four ICD-related genes in bladder cancer with increased immune cell infiltration and more prolonged survival. The study is valuable because it identifies a risk-scoring model, showing a correlation between high-risk scores based on four ICD-related genes and weak anti-tumour immune function. However, the evidence supporting the association of these genes and immunotherapy response is incomplete.
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Reviewer #1 (Public Review):
Summary:
The article explores the connection between immunogenic cell death (ICD)-related genes and bladder cancer prognosis, immune infiltration, and response to therapy. The study identifies a risk-scoring model involving four ICD-related genes (CALR, IL1R1, IFNB1, IFNG), showing a correlation between higher risk scores and weaker anti-tumor immune function.
Strengths:
The significance lies in the potential for personalized treatment guidance in bladder cancer. The establishment of a risk-scoring model to predict patient survival is noteworthy.
Weaknesses:
However, the identification of ICD-related genes is somewhat conventional, focusing on known genes regulating cancer immune response. To enhance the significance of the risk-scoring model, it would be better if the authors could validate the model across …
Reviewer #1 (Public Review):
Summary:
The article explores the connection between immunogenic cell death (ICD)-related genes and bladder cancer prognosis, immune infiltration, and response to therapy. The study identifies a risk-scoring model involving four ICD-related genes (CALR, IL1R1, IFNB1, IFNG), showing a correlation between higher risk scores and weaker anti-tumor immune function.
Strengths:
The significance lies in the potential for personalized treatment guidance in bladder cancer. The establishment of a risk-scoring model to predict patient survival is noteworthy.
Weaknesses:
However, the identification of ICD-related genes is somewhat conventional, focusing on known genes regulating cancer immune response. To enhance the significance of the risk-scoring model, it would be better if the authors could validate the model across various cancer types. The strength of evidence appears moderate, but broader applicability would strengthen the findings.
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Reviewer #2 (Public Review):
Immunogenic cell death (ICD) can lead to the release of factors such as DAMPs which promote an adaptive immune response. In the context of cancer, there is clear evidence of anti-tumour benefits as a result of ICD, perhaps induced by chemotherapy.
Lilong et al used TCGA data to explore whether a previously published 34 gene 'ICD-related' signature could stratify bladder cancer patients by prognosis and ultimately predict patient survival. The gene signature contains many genes involved in inflammation and immunity (IFNg, IL6, TNF, IL17A, TLR4, CD8B, etc) and those related to ICD (such as CALR, HMGB1, HSP, NLRP3, etc). The authors divide patients into 'ICD-high' and '-low' based on the expression of this gene set and find that 'ICD-high' is associated with longer survival in TCGA bladder cancer data. The …
Reviewer #2 (Public Review):
Immunogenic cell death (ICD) can lead to the release of factors such as DAMPs which promote an adaptive immune response. In the context of cancer, there is clear evidence of anti-tumour benefits as a result of ICD, perhaps induced by chemotherapy.
Lilong et al used TCGA data to explore whether a previously published 34 gene 'ICD-related' signature could stratify bladder cancer patients by prognosis and ultimately predict patient survival. The gene signature contains many genes involved in inflammation and immunity (IFNg, IL6, TNF, IL17A, TLR4, CD8B, etc) and those related to ICD (such as CALR, HMGB1, HSP, NLRP3, etc). The authors divide patients into 'ICD-high' and '-low' based on the expression of this gene set and find that 'ICD-high' is associated with longer survival in TCGA bladder cancer data. The authors further argue that ICD-high group responds better to PD1 therapies. From this 34-gene signature, it appears that LASSO regularisation and Cox analysis identifies a four-gene 'risk' signature (CALR, IL1R1, IFNB1, IFNG) which is associated with shorter patient survival and lower immunotherapy response rates. This is the primary finding. Their methodology is very similar to a publication in 2021 in Frontiers in Immunology instead in the context of head and neck squamous cell carcinoma. This paper is not referenced.
In terms of the strengths of the work, it is certainly plausible that the author's four gene signature has an association with survival in bladder cancer, at least based on the two datasets studied. However, the relatedness of their findings to ICD is unconvincing, and glaring omissions from the manuscript in terms of methods limit confidence in the work. The authors show a potential association with bladder cancer patient survival and their four gene signatures, but substantial revisions are required for this to be appropriately evidenced.
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