PONE-D-21-19069

A size and space structured model of tumor growth describes a key role for protumor immune cells in breaking equilibrium states in tumorigenesis

PLOS ONE

Dear Dr. Goudon,

Thank you for submitting your manuscript to PLOS ONE. We do apologize for the delay with which we are returning you the referee comments. Unfortunately, one of the referees had some health problems and had to delay his report.

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.

As suggested by one of the referees, I would strongly invite you to revise your manuscript along the referee comments to improve the readability of your manuscript and to reach the criteria for a publication in PLOS ONE.

Please submit your revised manuscript by Oct 15 2021 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: http://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,

Christophe Letellier, Ph.D., Prof.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please update your submission to use the PLOS LaTeX template. The template and more information on our requirements for LaTeX submissions can be found at http://journals.plos.org/plosone/s/latex.

3. Thank you for stating the following in the Acknowledgments/Funding Section of your manuscript: 

This work was supported by the French Government (National Research Agency, ANR)

through the “Investments for the Future” programs LABEX SIGNALIFE ANR-11-

LABX-0028 and IDEX UCAJedi ANR-15-IDEX-01

Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 

This work was supported by the French Government (National Research Agency, ANR) through the “Investments for the Future” programs LABEX SIGNALIFE ANR-11- LABX-0028 and IDEX UCAJedi ANR-15-IDEX-01. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf. 

4. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

Additional Editor Comments:

First, we do apologize the delay with which the referee comments are returned to you but one of the referees had some health problems and had to delay his report.

Second, both referees understood the potential of your work but they pointed out some problems in the presentation, inviting you to restructure your manuscript. I would like to invite you to follow this recommendations to improve the readability of your interesting work and thus, to have the positive feedback from the community it deserves.

[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: N/A

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: No

**********

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: No

**********

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: The authors are interested in immunoediting in tumors and in particular in the escape phase corresponding to an imbalance between an anti-tumor response and a pro-tumor response. The dynamics of the tumor are entirely driven by the immune system. The phenomena of angiogenesis and interactions with other healthy cells are ignored.

The proposed results are difficult to assess but appear biologically probable.

This work makes it possible to understand the failure of certain immunotherapies.

The fact that the solution to the cancer dynamic is based on the immune system does not allow us to understand the complexity of this pathology. It would have been interesting to combine this model with, for example, the process of angiogenesis and thus to test therapeutic combinations that already exist on the market.

Reviewer #2: The authors introduce a complex PDE model for anti-tumour/pro-tumour immune responses to cancer. Then, they consider a simplified version of this model (described by some simple ODEs) and for this model they investigate the existence and stability of various steady states. After that, the authors focus (I assume…) on the full model and try to find the equilibrium states. Then, the authors perform various numerical simulations showing what happens with model dynamics (although it is not clear whether they focus on the PDE or the ODE models) when various treatments are incorporated into the model.

Overall, the results have the potential to be very interesting. But the way they are presented makes it difficult to follow the flow of the paper. The authors should re-structure the paper and add more details, so that they “lead” the reader through their paper.

Below are some of the issues identified (which need to be addressed):

On page 11 the authors consider the case where “V and a are constant”. How is this possible when on the previous pages the authors show that “V” and “a” depend on “z” (see equations (1), (2) and (3))?

Page 14: I assume that the “healthy state (H)” is the one given by the zero vector on page 12? This needs to be made clear, since the notation (H) is never used on pages 12 and 13 ; only on page 14. Same comment about the other states: (NP) and (P).

Figure 3: It is not clear what is with the “expected equilibrium value a/\\delta (dotted)”. The tumour mass seems to approach this value at t=50 (panel (a)), t=10 (panel(b)), t=2.5 (panel (c)) and t=1.5 (panel(d)). The authors need to show on these panels what happens for very large time. Cutting the figures exactly at the time point where the tumour mass approaches this dotted line does not explain what is going on in Figure 3. Please re-do figure 3 to show also tumour dynamics for large time “t”.

The authors should also emphasise in the caption of this figure that there are two y-axes.

Finally, why is the continuous curve t-> mu1(t) but the dashed curve is t-> c (and not c(t))?

Figure 4 (c)-(d): I cannot see the dotted line. I can see only a dashed line…

Figure 4 (e )-(f): why the dashed curve is t->c while the continuous-dot curve is t->cr(t)? Why don’t you have t->c(t)?

Page 18: I don’t understand how the new section “Existence of equilibrium phases” is connected to the previous section. Does the new section correspond to the full model? How are the results in this Section different from the results in [24], [35], … Please explain very clearly what you do here. The reader cannot be let to “guess” the results of the section/paper, and how they connect with each other.

Figure 6: what represent the x-axis and y-axis in this figure? Same question for Figure 7.

Page 22: is “Emergent qualitative features …” a sub-section of the section “Results”? Or a parallel section? As discussed above, there is no explanation/flow for how the results connect with each other, so that the reader can follow easily this manuscript.

Figures 8,9,10, …14: Should I assume that these results are obtained with the PDE model, and the curves show space-averaged concentration values? Or do you show some simulations with an ODE model? Again, please don’t expect the reader to “guess” what you do here. You need to explain in detail what you show in these Figures.

Can the authors show also some space-time snapshots corresponding to the most interesting behaviours seen in Figures 8-10? (if these figures actually show spatially-averaged cell concentrations …)

Figures 16, 17, …: Same question as before: do the curves show space-averaged concentrations of cells (i.e., tumour mass and immune response)?

Are the Sections on pages 31, 34, 36 actually sub-sections of the “Results” section? It would be easier if sections/sub-sections/sub-subsections would be labelled.

**********

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.

A size and space structured model of tumor growth describes a key role for protumor immune cells in breaking equilibrium states in tumorigenesis

PONE-D-21-19069R1

Dear Dr. Goudon,

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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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,

Christophe Letellier, Ph.D., Prof.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for having addressed the referee comments which are recommending now to publish your manuscript.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. 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: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

4. 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: (No Response)

**********

5. 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: (No Response)

**********

6. 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: The authors have provided the necessary answers and clarifications to their work. The model is able to explain the dynamics of the complex interaction between the immune system and the tumour. However, I understand the need to simplify the tumour models, but in the future we cannot avoid introducing a system that takes into account the host and the toxicity of such treatments, particularly in the last part dealing with treatment strategies. Indeed, whether it is for checkpoint inhibitors which suffer in clinical practice from side effects sometimes so important that they cause a break or a cessation or CAR-T cells causing systemic hyperinflammation, it will be necessary and valuable to introduce these toxicities observed in clinical practice in order to obtain an efficient individualised strategy.

Reviewer #2: (No Response)

**********

7. 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