CD36 and Its Role in Regulating the Tumor Microenvironment

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Thank you again for considering my previous review. I think this review article is very informative for the field, where several researchers will cite this review. I only have minor grammatical revision suggestions, as indicated below. 

Line 75 space between “domain” and “can” is too wide, reduce by one space

Line 81 create a space between “entrance 1” and “entrance 2”

Lines 85-86, please use another word to replace different, the word different is used 3 times in one sentence. Perhaps use the words “various”, “several”, “many”.

Author Response

Dear Reviewer 1,

We thank you very much for considering our manuscript, so as to your positive comments and constructive suggestions. Accordingly, we have revised the manuscript based on your suggestion. Responses to specific comments are addressed below:

Line 75, space between “domain” and “can” is too wide, reduce by one space

Response: We thank for this suggestion. We have reduced by one space between “domain” and “can”.

Line 81, create a space between “entrance 1” and “entrance 2”

Response: We thank for this suggestion. We have created a space between “entrance 1” and “entrance 2”

Line 85-86, please use another word to replace different, the word different is used 3 times in one sentence. Perhaps use the words “various”, “several”, “many”.

Response: We thank for this suggestion. We have changed the sentence to "The expression level of CD36 is various in different cell types, and it performs diverse functions."

Thanks again for your positive comments and encouragement.

Yours Sincerely,

Xinzhi Liao

Author Response File: Author Response.docx

Reviewer 2 Report (Previous Reviewer 2)

Paper improved and can be published.

Author Response

Dear Reviewer 2,

We thank you very much for considering our manuscript.

Thanks again for your positive comments and encouragement.

Yours Sincerely,

Xinzhi Liao

Author Response File: Author Response.docx

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Review

CD36 and its role in regulating tumor microenvironment 2

Thank you for the chance to review your manuscript. I thought that the authors did an exceptional job at comprehensively presenting the functional aspects of CD36. I appreciated the authors’ focus on the role of CD36 in the tumor microenvironment, while including important details about several cell types: tumor-associated immune cells, Treg cells, CD8+ T cells, and macrophages. Also, the authors presented an interesting perspective about CD36 functions in cancer-associated fibroblasts, while providing molecular targets of potential therapies. Overall, the review was easy to read, and also provided the reader with new information about signaling pathways deserving of more study.

Major revisions

No major revisions to report.

Minor revisions

Line 12, maybe the authors should delete “and” before the word thrombospondin-2

Line 20, maybe the authors should delete “and”, because it is not appropriate to start a sentence with “And”

Line 34, perhaps change the phrase “correct the” to “alter”; delete “the” in the sentence

Line 39, maybe the authors should delete “and” to begin the sentence with “Feeding…”

Lines 90, 106, please italicize “in vivo” in the sentences

Line 106, please change “In the in vivo experiments conducted in mice…” to “In vivo mouse experiments indicated that CD36 deficiency impaired the influence of diet on Treg cells.”

Author Response

please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Dear authors,

your paper needs some improvements, mainly in the exposure and formulation of certain sentences, or in the interpretation of some results.

As such, 

You are using a large number of abbreviations, which should be explained; I suggest to add a brief list of abbreviations and their full names, at the beginning of the paper, before the introduction. 

Some formulations need a bit of some corrections, other are unclear, such as:

L26 “The tumor microenvironment (TME) includes proliferating tumor cells, fibroblasts, immune-related cells, tumor micro-vessels, and the secreted cytokines” à It also includes extracellular matrix components, to be added…

L 39 “And feeding palmitic acid diet to promote oral cancer and melanoma metastasis in mice also requires the mediation of CD36[7]. “ The sentence start with an “and” that seems not justified; The phrase should be re-written, I think “Promoting oral cancer or melanoma metastasis in mice, by using palmitic acid diet, requires (or, better, involves) the mediation of CD36."

L84 “significant upregulation of the number and function of Treg cells, which is a key factor contributing to the failure of anti-infection immunity and anti-tumor immunity” Upregulation can refer to the number of molecules (generally, proteins, such as, for instance, receptors, or other molecules in the cell), but not to the their function; should be rephrased…  

 L95 “Moreover, immunotherapy administered in combination with anti-PD-1mAb further dampened tumor development and extended the survival of 96 TregCD36-/- mice[25]. “  This phrase does not seem to by suggestive of the role of CD36. It’s about double-defective CD36 – so without the presence of the molecule there. Maybe you can analyze the source and perhaps have a comparison with mouse with normal CD36 expression?  

L100 “In addition, CD14+CD36hi 100 monocytes can present TGF-β and retinol to induce differentiation and…”  The mentioned paper speaks of  retinoic acid, which represent a different chemical entity than retinol; also, the mentioned authors do not speak of presentation of retinoic acid (as it can be the case with TGF-β which is a protein). The description of the roles of molecule in this phrase is erroneous. Please revise.

 I suggest to add Tanase C et. al “CD36 and CD97 in Pancreatic Cancer versus Other Malignancies” in Int J Mol Sci. 2020 Aug 6;21(16):5656. doi: 10.3390/ijms21165656., where a thorough analysis of this molecule was performed, and its role in tumor metastasis was examined, as well as in other mechanisms.

The titles of 6.2 and 6.3 are identical. I suppose 6.3 is on the formation of Vascular Mimicry.  Please correct that.  

Author Response

please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

This review addresses an important molecule that regulates the tumor microenvironment in several different ways, through several cell types. In its current form, however, it is not a review warranting publication due to its extremely high level overview of all topics discussed. Data is not discussed in any comprehensive way. Only generalized conclusions are provided. In several places, the actual cancer type from which a statement is derived is not even mentioned. In sections where conflicting data are reported, reasons as to why are not adequately discussed. The text jumps from study to study without any appreciable interpretation or synthesis.

 The first figure of the paper should be a detailed structure of CD36, including illustrations of all know protein binding sites and modification regions. This should include any known changes in function modifications have on its function.

 After the structure section (section 2), there should be a section on normal functions of CD36. Alternatively, each following section should begin with a paragraph or two on the normal function of CD36 within each function.

 The mechanisms of most functions discussed are not clear from the text. For example, is CD36 actually upregulated in immune cells? If so, how? Is there something secreted from tumor cells that upregulate CD36?

  In the current figure 1, the actual mechanism of tumor-promotion by each type of immune cell is not readily evident in the figure. For example, how does OXPHOS in TAMS contribute to tumor growth?

 This review may be focused in several ways such that more depth can be provided. One such way would be to focus only on a subset of cancers, such as hormonally driven tumors (breast, prostate, ovarian, prostate) or obesity-driven tumors (although the latter may be too broad too).  Another way to focus would be to concentrate only on immune-related functions, angiogenesis or EMT, but not all.

 The English grammar, and word choices, require review and significant editing.

Minor comments:

Acronyms are not defined at first use in the text of the manuscript.

Author Response

please see the attachment.

Author Response File: Author Response.pdf