Increased Apolipoprotein A1 Expression Correlates with Tumor-Associated Neutrophils and T Lymphocytes in Upper Tract Urothelial Carcinoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article titled "Increased apolipoprotein A1 expression correlates with tumor-associated neutrophils and T lymphocytes in upper tract urothelial carcinoma" presents novel insights into the immunomodulatory effects of apolipoprotein A1 (Apo-A1) within the tumor microenvironment of upper tract urothelial carcinoma (UTUC). It highlights a correlation between elevated Apo-A1 levels, increased tumor-associated neutrophils, and the suppression of T lymphocyte proliferation, suggesting potential therapeutic targets for UTUC treatment.

Strengths:

• Novelty and Interest: The study provides new evidence linking Apo-A1 expression with the modulation of neutrophils and T cells in UTUC, an area not extensively explored before. This offers fresh avenues for immunotherapy strategies.
• Methodology: The comprehensive methodology, including proteomic analysis, flow cytometry, and statistical analysis, supports the study's findings robustly.

Areas for Improvement:

• Sample Size: The study might benefit from a larger sample size to enhance the statistical significance and generalizability of the findings.this should be better discussed in limitations.
• Longitudinal Data: Including longitudinal studies could help understand the dynamics of Apo-A1 expression and its immunomodulatory effects over the progression of UTUC.
• Mechanistic Insights: While the correlation is well-established, deeper mechanistic insights into how Apo-A1 modulates the tumor microenvironment would strengthen the study's impact.
• Clinical Relevance: Expanding on how these findings can directly translate into clinical practice or guide therapeutic intervention would be valuable.
• Comparative Analysis: A comparison with other types of urothelial carcinoma or cancers could provide context on the specificity and potential wider implications of Apo-A1's role in cancer immunology.

• Introduction Improvement: Updating the introduction to incorporate the most recent findings and theories in the field can set a stronger context for the study, highlighting its relevance and urgency. It helps in framing the research question more compellingly, drawing a direct line from existing knowledge gaps to the study's objectives. Citing the article with PMID: 36964236 in your introduction would be highly beneficial. This review offers a gender-specific, evidence-based clinical guide on diagnosing, screening, surveillance, and counseling of UTUC patients with Lynch syndrome (LS). It highlights the significant association of gene mutations with different cancers based on gender and underscores the necessity of a multidisciplinary approach for managing LS, emphasizing the distinct impacts of the same mutation based on the patient's gender

• Discussion Enhancement: In the discussion, a more thorough comparison with recent studies could provide a deeper analysis of how the findings align with or diverge from current understanding. This could involve exploring new hypotheses, potential mechanisms, or implications for treatment strategies that have emerged in the literature since the initial drafting of the article. Please cite and discuss the following: PMID: 37680219; PMID: 35383431.

In summary, the study makes a significant contribution to the understanding of UTUC's immunological landscape, with implications for targeted therapies. Addressing the mentioned areas for improvement could further enhance its publication merit.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

In this paper, Chang et al aimed to investigate the relationship between neutrophils and lymphocytes in tumor and blood samples from patients with UTUC. There are some major issues that question the suitability of the manuscript:

1) The authors do not show the correlation between serum Apo-A1 levels and tumor infiltrating neutrophils, as stated in the title, line 252 and the conclusions section, but only the correlation between serum Apo-A1 and TILs.

2) The only correlation shown is between serum Apo-A1 and serum neutrophils, between all subjects. Why was pooled blood used for this analysis and not just blood from UTUC patients?

3) The authors do not clearly define inclusion and exclusion criteria for subject selection. The results would not be valid if the subjects had any comorbidity or had received any medication that could potentially affect the levels of the immune cells or Apo-A1.

Minor comments:

1) Line 42-43. Please provide more details on the higher aggressiveness of UTUC vs bladder cancer.

2) The Materials and Methods section requires detailed description of procedures, in order to be reproducible (handling of tumors and blood, storage, quantities etc)

3) Please add details on the method used to measure serum levels of Apo-A1

4) The statistical description is incomplete. Please add the Spearman's correlation test and the software used to make the heatmap of suppl. Figure 1.

5) Figure 3: The authors could include a graph showing the levels of tumor infiltrating neutrophils and T-lymphocytes. 

6) The supplementary figure can be added in the main manuscript

 

Comments on the Quality of English Language

Extensive editing of English language is required.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

I congrats with the authors for this interesting manuscript.

Line 80 “Including endoscopic biopsy and surgical resection of urinary tract cancers.” Please better describe these procedures: Diagnostic RIRS + biopsy and Nephroureterectomy?

Line 82: “The hematological data about the proportion of neutrophils and 82 lymphocytes in peripheral bloods of study participants was shown in Table 1.” Please state if all the hematological samples have been processed by the same laboratory. Otherwise please expand the limitations session.

Discussion must be implemented. For example, do you think that this could become a clinical useful biomarkers for upper and lower tract urothelial carcinomas? ( i.e. doi: 10.3390/cancers14061520. - doi: 10.3390/ijerph19159648. )

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Upon reviewing the revised version of the manuscript, I can affirm that the authors have effectively addressed the concerns raised in the previous review. They have made significant improvements to the text, clarified ambiguous points, and provided additional data that strengthen the claims of their study. The research now presents a more robust and comprehensive analysis, making a significant contribution to the field. Therefore, I recommend that the revised version of the manuscript be considered for publication. 

Reviewer 2 Report

Comments and Suggestions for Authors

I would like to thank the authors for their meticulous work in addressing my comments, adding the figures and improving the manuscript, that is now suitable for publication.