Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy

Samia S. Alkhalil; Taghreed N. Almanaa; Raghad A. Altamimi; Mohnad Abdalla; Amr Ahmed El-Arabey

doi:10.1371/journal.pone.0312590

Peer Review History

Original SubmissionApril 23, 2024
26 Jun 2024 Decision Letter - Elham Samami, Editor PONE-D-24-16304Microbiomes and uterine corpus endometrial cancer: A novel crosstalk between abnormal gut microbiota and immunotherapyPLOS ONE Dear Dr. El-Arabey, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Aug 10 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Dear Authors, We are pleased to inform you that your manuscript has been accepted with minor revisions. We would like to bring the following points to your attention for improvement: Title Adjustment: It is necessary to modify the title to better reflect the computational aspects of your work. This will help highlight the methodology and analytical approaches used in your study. Elaboration on Databases: Your study heavily relies on existing databases such as TCGA, TIMER2.0, and Cancer-mbQTL. Please provide a more detailed description in the Methods section, specifically elaborating on how these databases were linked and utilized to support your research findings. Statistical Analysis: To strengthen your conclusions, it is recommended to incorporate inferential statistical tests. These tests should assess the significance of differences in mutation frequencies and immune cell infiltration, providing a more robust foundation for your findings. Correlation Analysis: The use of Pearson correlation assumes a linear relationship between variables, which may not accurately capture the complex, nonlinear interactions inherent in biological systems. Consider discussing alternative methods that might better represent these interactions. Model Validation: To prevent overfitting, we recommend implementing cross-validation techniques, such as k-fold cross-validation, and using regularization methods like LASSO or ridge regression. Additionally, independent validation with separate datasets is advised to ensure the robustness of your findings and to avoid large dataset overfitting. Broader Context in Discussion: The Discussion section consequently should include a more comprehensive analysis of microbial interactions and their potential effects on the tumor microenvironment (TME). This will provide a deeper context for your results and implications. We look forward to receiving your revised manuscript. Should you have any questions or need further clarification, please do not hesitate to contact us. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No Reviewer #2: N/A ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: It's needed for title to point towrad the computational nature of this work. The study heavily relies on existing databases such as TCGA, TIMER2.0, and Cancer-mbQTL and it is needed to elaborate more in methods ,what was the process of linking the function of these databases. Incorporating inferential statistical tests to assess the significance of differences in mutation frequencies and immune cell infiltration would provide more robust conclusions. Pearson correlation assumes a linear relationship between variables, which may not accurately represent the complex, nonlinear interactions in biological systems. Implementing cross-validation techniques, such as k-fold cross-validation, and using regularization methods (e.g., LASSO, ridge regression) can help prevent overfitting. Independent validation with separate datasets is also recommended to avoid large dataset overfitting. Broader microbial interactions and their effects on the TME is needed to be discussed in discussion. Reviewer #2: Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) (Limit 200 to 20000 Characters) ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0312590.r001
Revision 1
2 Sep 2024 Author Response The academic Editor, 9 th August, 2024 Plos One Subject: (Revised manuscript (Ref. PONE-D-24-16304) and our response to Reviewer’s comments). Dear Prof. Elham Samami With great enthusiasm, we are submitting our revised manuscript entitled, “Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy” by Samia S. Alkhalil 1* , Taghreed N Almanaa 2, Raghad A Albedair 3, Mohnad Abdalla4 and Amr Ahmed El-Arabey5*, for consideration publication in Plos One. We are very grateful for the constructive and positive feedback of the reviewers and editor. Following the reviewers’ suggestions, we have revised our work and manuscript against the reviewer’s comment. Please see the below document titled “Reviewers’ comments/questions and their answers”, in which we have included detailed point-to-point responses. We believe that we have fully addressed all concerns raised in the original submission, and the current revised manuscript has been substantially strengthened and improved for possible publication in Plos One. We sincerely hope this revised manuscript would satisfy both the reviewers and the editor and would be happy to answer any additional questions anytime. Thank you for your valuable time in reviewing our work, and look forward to your reply. Looking forward to hearing from you. Kind Regards, Amr Ahmed El-Arabey (Corresponding author) Email: ph.amrcapa@gmail.com Reviewers’ comments/questions and their answers 1. Title Adjustment: It is necessary to modify the title to better reflect the computational aspects of your work. This will help highlight the methodology and analytical approaches used in your study. Response: Thank you so much for your positive feedbacks. As suggested by the reviewer, we revised our manuscript (Red discoloration in the manuscript): Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy” 2. Elaboration on Databases: Your study heavily relies on existing databases such as TCGA, TIMER2.0, and Cancer-mbQTL. Please provide a more detailed description in the Methods section, specifically elaborating on how these databases were linked and utilized to support your research findings. Response: Done: (Red discoloration in the manuscript): 3. Statistical Analysis: To strengthen your conclusions, it is recommended to incorporate inferential statistical tests. These tests should assess the significance of differences in mutation frequencies and immune cell infiltration, providing a more robust foundation for your findings. Response: In the current proposal we used the Cancer-mbQTL database to discover immune cells from CIBERSORT deconvolution of TCGA data that correlate with the abundance levels of microbes in tumor tissues of UCEC patients (designated as cancer microbiome quantitative trait loci, cancer-mbQTL). This comprehensive mbQTL database aids in successfully evaluating the influence of gene mutations on cancer microbiome characteristics, establishing a new paradigm for understanding the function of risk genetic mutations in human malignancies. 4. Correlation Analysis: The use of Pearson correlation assumes a linear relationship between variables, which may not accurately capture the complex, nonlinear interactions inherent in biological systems. Consider discussing alternative methods that might better represent these interactions. Response: The Pearson correlation assumes that the relationship between variables is linear. If the relationship is not linear, Pearson’s correlation may not accurately represent the association. In this regard, we used Spearman correlation to determine the relationship between microbial abundance and immune cell infiltration in uterine corpus endometrial cancer using CIBERSORT method. Associations with FDR < 0.05 were deemed statistically significant. Kraken-derived normalized microbial abundances of TCGA patients were collected from the Cancer Microbiome. This comprehensive mbQTL database aids in successfully evaluating the influence of gene mutations on cancer microbiome characteristics, establishing a new paradigm for understanding the function of risk genetic mutations in human malignancies. 5. Model Validation: To prevent overfitting, we recommend implementing cross-validation techniques, such as k-fold cross-validation, and using regularization methods like LASSO or ridge regression. Additionally, independent validation with separate datasets is advised to ensure the robustness of your findings and to avoid large dataset overfitting. Response: In the current proposal, we provide CIBERSORT, a technique for defining the cell composition of complex tissues using gene expression data. When applied to enumerating hematopoietic subsets in RNA mixes from fresh, frozen, and fixed tissues, including solid tumors, CIBERSORT outperformed other approaches in terms of noise, unknown mixture content, and closely related cell types. CIBERSORT should facilitate large-scale investigation of RNA mixtures for biological biomarkers and medicinal targets. Besides, there are limited bioinformatic database of microbiota to introduce validation with separate database. Reference: Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015 May;12(5):453-7. doi: 10.1038/nmeth.3337. 6. Broader Context in Discussion: The Discussion section consequently should include a more comprehensive analysis of microbial interactions and their potential effects on the tumor microenvironment (TME). This will provide a deeper context for your results and implications. Response: Done: (Red discoloration in the manuscript): https://doi.org/10.1371/journal.pone.0312590.r002
24 Sep 2024 Decision Letter - Elham Samami, Editor PONE-D-24-16304R1Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapyPLOS ONE Dear Dr. El-Arabey, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Nov 08 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Elham Samami Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Please provide a new draft of the paper with an open review tracker that highlights the recent changes made since the previous submission. [Note: HTML markup is below. Please do not edit.] [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0312590.r003
Revision 2
25 Sep 2024 Author Response The academic Editor Plos One Subject: (Revised manuscript (Ref. PONE-D-24-16304) and our response to Reviewer’s comments). Dear Prof. Elham Samami With great enthusiasm, we are submitting our revised manuscript entitled, “Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy” by Samia S. Alkhalil 1* , Taghreed N Almanaa 2, Raghad A Albedair 3, Mohnad Abdalla4 and Amr Ahmed El-Arabey5*, for consideration publication in Plos One. We are very grateful for the constructive and positive feedback of the reviewers and editor. Following the reviewers’ suggestions, we have revised our work and manuscript against the reviewer’s comment. Please see the below document titled “Reviewers’ comments/questions and their answers”, in which we have included detailed point-to-point responses. We believe that we have fully addressed all concerns raised in the original submission, and the current revised manuscript has been substantially strengthened and improved for possible publication in Plos One. We sincerely hope this revised manuscript would satisfy both the reviewers and the editor and would be happy to answer any additional questions anytime. Thank you for your valuable time in reviewing our work, and look forward to your reply. Looking forward to hearing from you. Kind Regards, Amr Ahmed El-Arabey (Corresponding author) Email: ph.amrcapa@gmail.com Reviewers’ comments/questions and their answers 1. Title Adjustment: It is necessary to modify the title to better reflect the computational aspects of your work. This will help highlight the methodology and analytical approaches used in your study. Response: Thank you so much for your positive feedbacks. As suggested by the reviewer, we revised our manuscript (Red discoloration in the manuscript): Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy” 2. Elaboration on Databases: Your study heavily relies on existing databases such as TCGA, TIMER2.0, and Cancer-mbQTL. Please provide a more detailed description in the Methods section, specifically elaborating on how these databases were linked and utilized to support your research findings. Response: Done: (Red discoloration in the manuscript): 3. Statistical Analysis: To strengthen your conclusions, it is recommended to incorporate inferential statistical tests. These tests should assess the significance of differences in mutation frequencies and immune cell infiltration, providing a more robust foundation for your findings. Response: In the current proposal we used the Cancer-mbQTL database to discover immune cells from CIBERSORT deconvolution of TCGA data that correlate with the abundance levels of microbes in tumor tissues of UCEC patients (designated as cancer microbiome quantitative trait loci, cancer-mbQTL). This comprehensive mbQTL database aids in successfully evaluating the influence of gene mutations on cancer microbiome characteristics, establishing a new paradigm for understanding the function of risk genetic mutations in human malignancies. 4. Correlation Analysis: The use of Pearson correlation assumes a linear relationship between variables, which may not accurately capture the complex, nonlinear interactions inherent in biological systems. Consider discussing alternative methods that might better represent these interactions. Response: The Pearson correlation assumes that the relationship between variables is linear. If the relationship is not linear, Pearson’s correlation may not accurately represent the association. In this regard, we used Spearman correlation to determine the relationship between microbial abundance and immune cell infiltration in uterine corpus endometrial cancer using CIBERSORT method. Associations with FDR < 0.05 were deemed statistically significant. Kraken-derived normalized microbial abundances of TCGA patients were collected from the Cancer Microbiome. This comprehensive mbQTL database aids in successfully evaluating the influence of gene mutations on cancer microbiome characteristics, establishing a new paradigm for understanding the function of risk genetic mutations in human malignancies. 5. Model Validation: To prevent overfitting, we recommend implementing cross-validation techniques, such as k-fold cross-validation, and using regularization methods like LASSO or ridge regression. Additionally, independent validation with separate datasets is advised to ensure the robustness of your findings and to avoid large dataset overfitting. Response: In the current proposal, we provide CIBERSORT, a technique for defining the cell composition of complex tissues using gene expression data. When applied to enumerating hematopoietic subsets in RNA mixes from fresh, frozen, and fixed tissues, including solid tumors, CIBERSORT outperformed other approaches in terms of noise, unknown mixture content, and closely related cell types. CIBERSORT should facilitate large-scale investigation of RNA mixtures for biological biomarkers and medicinal targets. Besides, there are limited bioinformatic database of microbiota to introduce validation with separate database. Reference: Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015 May;12(5):453-7. doi: 10.1038/nmeth.3337. 6. Broader Context in Discussion: The Discussion section consequently should include a more comprehensive analysis of microbial interactions and their potential effects on the tumor microenvironment (TME). This will provide a deeper context for your results and implications. Response: Done: (Red discoloration in the manuscript): https://doi.org/10.1371/journal.pone.0312590.r004
10 Oct 2024 Decision Letter - Elham Samami, Editor Interactions between microbiota and uterine corpus endometrial cancer: A bioinformatic investigation of potential immunotherapy PONE-D-24-16304R2 Dear Dr. El-Arabey, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Elham Samami Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0312590.r005
Formally Accepted
18 Oct 2024 Acceptance Letter - Elham Samami, Editor PONE-D-24-16304R2 PLOS ONE Dear Dr. El-Arabey, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of . Elham Samami Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0312590.r006

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