Role of Nutrients Regulating Myeloid Derived Suppressor Cells in Cancer: A Scoping Review

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Comments and Suggestions for Authors

Myeloid-derived suppressor cells (MDSC) are immature cells with immunosuppressive functions, involved in tumor growth and metastasis. Certain nutrients like selected vegetables, icariin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea can reduce MDSC and their immunosuppressive ability, potentially improving cancer prognosis. Diets such as Mediterranean, ketogenic, low-glycemic index, high-fiber, plant-based, traditional Asian, and anti-inflammatory diets may have protective effects against cancer. The paper reviews various studies showing the impact of nutrients on MDSC, suggesting potential benefits in cancer prevention and treatment. Specific comments:

1.          The introduction provides a good overview of MDSC, but it could benefit from a clearer explanation of the specific role of nutrients in regulating these cells.

2.          The paper mentions various studies, but it would be helpful to include a more detailed comparison of their methodologies and findings.

3.          The methodology section could be expanded to include more information about the selection criteria for the studies reviewed.

4.          Why were certain nutrients chosen for this review? Are there other nutrients that could also impact MDSC?

5.          Adding more figures and tables to summarize the data would make the paper more reader-friendly.

6.          The discussion section could be expanded to include more about the potential mechanisms through which nutrients affect MDSC.

7.          The paper mentions potential clinical implications, but it would be helpful to provide more specific examples or case studies.

8.          What are the next steps for research in this area? The paper could benefit from a more detailed discussion of future research directions.

 

 

Author Response

Reviewer 1

Myeloid-derived suppressor cells (MDSC) are immature cells with immunosuppressive functions, involved in tumor growth and metastasis. Certain nutrients like selected vegetables, icariin, retinoic acid, curdlan, active vitamin D, soy isoflavones, and green tea can reduce MDSC and their immunosuppressive ability, potentially improving cancer prognosis. Diets such as Mediterranean, ketogenic, low-glycemic index, high-fiber, plant-based, traditional Asian, and anti-inflammatory diets may have protective effects against cancer. The paper reviews various studies showing the impact of nutrients on MDSC, suggesting potential benefits in cancer prevention and treatment. Specific comments:

 

Comment: 1. Introduction provides a good overview of MDSC, but it could benefit from a clearer explanation of the specific role of nutrients in regulating these cells.

Reply: This issue was addressed in the introduction, in which we explained the specific role of some nutrients regulating MDSC, such as fibers, vitamin D, or retinoic acid (lines 76-83). However, we have improved it with additional nutrients such as amino acids L-arginine and glutamine, as well as glucose in lines 83-92, which has been supported with seven new references.

 

Comment: 2. The paper mentions various studies, but it would be helpful to include a more detailed comparison of their methodologies and findings.

Reply: Comparison of methodologies and findings of the seven studies evaluated in this review are found in Table 1. Following the second reviewer’s suggestion, we have re-written some parts of the text from Table 1 to show relevant information, especially that related to methodology and findings of the seven studies, to make the table more concise.

 

Comment: 3. The methodology section could be expanded to include more information about the selection criteria for the studies reviewed.

Reply: The second reviewer suggested to make the methodology section more concise and informative. However, we have included more information in section 2.2 (eligibility criteria) to explain why we used specific exclusion criteria (lines 109-120). In this sense, we excluded studies (i) different from original articles, such as conference abstracts or books, because they did not report novel findings, (ii) written in a different language from English or Spanish because of the difficulty to understand the text content, (iii) published before 2015 since, to the best of our knowledge, there were no studies addressing the impact of nutrients of MDSC before that year, and (iv) without full text access because it was necessary to get access to the full manuscript to check the all the results.

 

Comment: 4. Why were certain nutrients chosen for this review? Are there other nutrients that could also impact MDSC?

Reply: The nutrients chosen for this review were not selected intentionally but are those identified from different studies after applying the inclusion and exclusion criteria outlined in this review, which we believe are the most suitable for covering the current state of this topic.

To the best of our knowledge, currently there are no other nutrients (investigated or under investigation) that impact on MDSC, but we think that there may be other nutrients with this function. It would be very interesting to evaluate those nutrients that have demonstrated a beneficial role in certain types of cancers, but whose effects on the immune system, including their impact on MDSCs, remain currently unknown.

 

Comment: 5. Adding more figures and tables to summarize the data would make the paper more reader-friendly.

Reply: As mentioned before, we have improved Table 1 to better summarize the data and make the information about the seven articles more concise and reader friendly. We hope this will be sufficient given the limited number of original articles published on this topic to date. Regarding the figures, there is one that summarizes the article search process, and we think that adding others —such as those related to the functions of MDSC in cancer—would not be meaningful, as it would deviate from the purpose of this review (to evaluate how nutrients contribute to the immunomodulation of MDSC).

 

Comment: 6. The discussion section could be expanded to include more about the potential mechanisms through which nutrients affect MDSC.

Reply: Since we mentioned in the discussion section some mechanisms through which arginine, glutamine, glucose, fatty acids, cholesterol and vitamin D affect MDSC, we have improved it by mentioning other mechanisms affecting MDSC, such as those involving all trans-retinoic acid (lines 257-259), vitamin E (lines 259-261), EGCG (lines 293-296), and curdlan (307-311).

 

Comment: 7. The paper mentions potential clinical implications, but it would be helpful to provide more specific examples or case studies.

Reply: In the conclusion section, we have provided some examples of possible studies with potential clinical implications regarding the impact of nutrients in MDSC (lines 353-360).

 

Comment: 8. What are the next steps for research in this area? The paper could benefit from a more detailed discussion of future research directions.

Reply: In the conclusion section, we have provided detailed future steps in this area to stablish nutrients as regulators of MDSC in cancer (lines 337-346). In addition, we found some inconsistencies that made the conclusion difficult to understand, so we have restructured the text in order to make it easier to comprehend.

Reviewer 2 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

Although this revised manuscript has improved from its first submission, and nutrient regulation of myeloid-derived suppressor cells is worth a review, there are still many issues that need adjustment to scientific writing.

 

1). It is suggested to reposition lines 52-57 to the last paragraph of the introduction to make a stronger hypothesis/goal of the paper: ‘Altogether, it is of general interest in the field of MDSC to improve the knowledge and understanding about those nutrients factors that (i) benefit the accumulation of MDSC in the tumor microenvironment (TME, and (ii) limit the acquisition of their immunosuppressive capacity, which is a potential line of investigation towards the development of therapies that prevent the tumor from growing. Therefore, we aimed to assess a scoping review to discuss how the relationship between nutrients and MDSC could influence the predispositioned oncological settings.’

2). The methods section needs a major overhaul (as was suggested earlier). It should be clear what inclusion and exclusion criteria were applied. Making a supplementary Table showing the search protocols for each mayor database is not needed: the methods should be self-explanatory. Do NOT use bullet-points in this section but write and explain in essential wording the selection criteria and the databases searched. There is no need to repeat the aim of the search (this needs to be added to the paragraph under the previous point). You can mention a more general search strategy (for all databases), based on a more evidence-based approach, like PICO, but have it integrated in the text, and do not list it as bullet-points. The methods are the essential part of your identification of relevant papers- even for a scoping review - so it is important to make this section scientific, concise, correct and informative. The methods need major changes.

3). In relation point 2), there is duplicate information in Table 1 and Figure 1: It is suggested to add the most relevant general ‘search’ key (not ‘research’ as the table indicated for each dbase) to the methods section. Table 1 should not be part of the main manuscript, but if you feel like it should be a supplementary table. The column ‘filters’ is basically a inclusion/exclusion criteria that should be mentioned in the methods. The data in the column with number of documents is already mentioned in Figure 1, and altogether Table 1 seems to just duplicate the writing, making it non-essential, thus only a supplementary Table. Figure 1 could include for the identification part, the number of excluded papers per specific database, then mentioning the total dismissed.

4). Abstract should mention ‘7 identified papers of which 6 mouse model studies and 1 human trial study, before continuing - from line 22- with the actual studies the statements are based on.

5). Table 2, needs attention in having the text displayed be more concise. Also, why abbreviate selected vegetables? The lines ‘in lung cancer patients’ is deceptive as these studies do NOT include human patients, but are using mouse; delete and reformulate. This goes for ALL the entries! State the observed results of nutrients or foods that are relevant. Not the hypothetical results on humans done by the authors!

Additional suggestions:

6). Line 34, reformulate ‘other mechanisms are different’

7). Line 52, TME is not defined upon first mention.

8). Line 59, what does ‘it’ refer to? ‘Deficit of nutrient’? Be correct, maybe use ‘nutrient deficiency’ instead?

9). Line 87, define ‘Treg’

10). Line 88, reformulate ‘also have influenced’

11). Line 94, reformulate ‘on oncological settings’

12). Line 240, reformulate ‘also lead MDSC development’

13). Line 242, specify and be more clear ‘some food components’

14). Lines 273/274: ‘Importantly, the studies evaluated in this review also analyzed other cells involved in the tumor mechanisms, such as Tregs, CD8+ T cells, or NK cells.’ while that might be true, it is better to devote some more writing to the explanation on these classes of cells (see also point 8) as this is might not be familiar to the general reader, and make this issue a sub result of this scoping review, giving the paper more weight.

15). Line 306, reformulate ‘it has been shown a relationship’

Comments on the Quality of English Language

Although this revised manuscript has improved from its first submission, and nutrient regulation of myeloid-derived suppressor cells is worth a review, there are still many issues that need adjustment to scientific writing.

 

1). It is suggested to reposition lines 52-57 to the last paragraph of the introduction to make a stronger hypothesis/goal of the paper: ‘Altogether, it is of general interest in the field of MDSC to improve the knowledge and understanding about those nutrients factors that (i) benefit the accumulation of MDSC in the tumor microenvironment (TME, and (ii) limit the acquisition of their immunosuppressive capacity, which is a potential line of investigation towards the development of therapies that prevent the tumor from growing. Therefore, we aimed to assess a scoping review to discuss how the relationship between nutrients and MDSC could influence the predispositioned oncological settings.’

2). The methods section needs a major overhaul (as was suggested earlier). It should be clear what inclusion and exclusion criteria were applied. Making a supplementary Table showing the search protocols for each mayor database is not needed: the methods should be self-explanatory. Do NOT use bullet-points in this section but write and explain in essential wording the selection criteria and the databases searched. There is no need to repeat the aim of the search (this needs to be added to the paragraph under the previous point). You can mention a more general search strategy (for all databases), based on a more evidence-based approach, like PICO, but have it integrated in the text, and do not list it as bullet-points. The methods are the essential part of your identification of relevant papers- even for a scoping review - so it is important to make this section scientific, concise, correct and informative. The methods need major changes.

3). In relation point 2), there is duplicate information in Table 1 and Figure 1: It is suggested to add the most relevant general ‘search’ key (not ‘research’ as the table indicated for each dbase) to the methods section. Table 1 should not be part of the main manuscript, but if you feel like it should be a supplementary table. The column ‘filters’ is basically a inclusion/exclusion criteria that should be mentioned in the methods. The data in the column with number of documents is already mentioned in Figure 1, and altogether Table 1 seems to just duplicate the writing, making it non-essential, thus only a supplementary Table. Figure 1 could include for the identification part, the number of excluded papers per specific database, then mentioning the total dismissed.

4). Abstract should mention ‘7 identified papers of which 6 mouse model studies and 1 human trial study, before continuing - from line 22- with the actual studies the statements are based on.

5). Table 2, needs attention in having the text displayed be more concise. Also, why abbreviate selected vegetables? The lines ‘in lung cancer patients’ is deceptive as these studies do NOT include human patients, but are using mouse; delete and reformulate. This goes for ALL the entries! State the observed results of nutrients or foods that are relevant. Not the hypothetical results on humans done by the authors!

Additional suggestions:

6). Line 34, reformulate ‘other mechanisms are different’

7). Line 52, TME is not defined upon first mention.

8). Line 59, what does ‘it’ refer to? ‘Deficit of nutrient’? Be correct, maybe use ‘nutrient deficiency’ instead?

9). Line 87, define ‘Treg’

10). Line 88, reformulate ‘also have influenced’

11). Line 94, reformulate ‘on oncological settings’

12). Line 240, reformulate ‘also lead MDSC development’

13). Line 242, specify and be more clear ‘some food components’

14). Lines 273/274: ‘Importantly, the studies evaluated in this review also analyzed other cells involved in the tumor mechanisms, such as Tregs, CD8+ T cells, or NK cells.’ while that might be true, it is better to devote some more writing to the explanation on these classes of cells (see also point 8) as this is might not be familiar to the general reader, and make this issue a sub result of this scoping review, giving the paper more weight.

15). Line 306, reformulate ‘it has been shown a relationship’

Author Response

Although this revised manuscript has improved from its first submission, and nutrient regulation of myeloid-derived suppressor cells is worth a review, there are still many issues that need adjustment to scientific writing.

Comment: 1). It is suggested to reposition lines 52-57 to the last paragraph of the introduction to make a stronger hypothesis/goal of the paper: ‘Altogether, it is of general interest in the field of MDSC to improve the knowledge and understanding about those nutrients factors that (i) benefit the accumulation of MDSC in the tumor microenvironment (TME, and (ii) limit the acquisition of their immunosuppressive capacity, which is a potential line of investigation towards the development of therapies that prevent the tumor from growing. Therefore, we aimed to assess a scoping review to discuss how the relationship between nutrients and MDSC could influence the predispositioned oncological settings.’

Reply: We have relocated the sentence from lines 52-57 in the last paragraph of the introduction to make a stronger hypothesis and goal of this review. Now, the sentence in lines 93-98.

 

Comment: 2). The methods section needs a major overhaul (as was suggested earlier). It should be clear what inclusion and exclusion criteria were applied. Making a supplementary Table showing the search protocols for each mayor database is not needed: the methods should be self-explanatory. Do NOT use bullet-points in this section but write and explain in essential wording the selection criteria and the databases searched. There is no need to repeat the aim of the search (this needs to be added to the paragraph under the previous point). You can mention a more general search strategy (for all databases), based on a more evidence-based approach, like PICO, but have it integrated in the text, and do not list it as bullet-points. The methods are the essential part of your identification of relevant papers- even for a scoping review - so it is important to make this section scientific, concise, correct and informative. The methods need major changes.

Reply: All bullet points from this section have been removed. PICO sentences have been removed, but the text in now integrated as “For this, we have searched different studies to (i) identify nutrients that have effects on the proliferation and/or differentiation of MDSC, and (ii) identify dietary patterns that may be associated with better survival rates” (lines 105-107). In addition, inclusion and exclusion criteria have been rewritten to improve their integration in the text (section 2.2, lines 109-120).

As suggested by the reviewer, a supplementary table showing the search protocols for each mayor database is not needed, so we have removed Table 1 and section 2.3 (which was only used to mention Table 1). With this change, Table 2 has been named as Table 1. We have also removed section 2.4 because the terms used for the eligibility criteria are found in section 2.2.

We now think that this section is concise, correct and informative, and has been improved according to these suggestions.

 

Comment: 3). In relation point 2), there is duplicate information in Table 1 and Figure 1: It is suggested to add the most relevant general ‘search’ key (not ‘research’ as the table indicated for each dbase) to the methods section. Table 1 should not be part of the main manuscript, but if you feel like it should be a supplementary table. The column ‘filters’ is basically a inclusion/exclusion criteria that should be mentioned in the methods. The data in the column with number of documents is already mentioned in Figure 1, and altogether Table 1 seems to just duplicate the writing, making it non-essential, thus only a supplementary Table. Figure 1 could include for the identification part, the number of excluded papers per specific database, then mentioning the total dismissed.

Reply: Thank you for noticing. As explained in the previous comment, we have removed Table 1.

 

Comment: 4). Abstract should mention ‘7 identified papers of which 6 mouse model studies and 1 human trial study, before continuing - from line 22- with the actual studies the statements are based on.

Reply: We have included the following sentence in the suggested position at the abstract: “We identified 7 papers, of which 6 were murine model studies and only 1 was a human clinical trial” (lines 19-20).

 

Comment: 5). Table 2, needs attention in having the text displayed be more concise. Also, why abbreviate selected vegetables? The lines ‘in lung cancer patients’ is deceptive as these studies do NOT include human patients, but are using mouse; delete and reformulate. This goes for ALL the entries! State the observed results of nutrients or foods that are relevant. Not the hypothetical results on humans done by the authors!

Reply: Abbreviation of ‘selected vegetables’ and hypothetical results on humans (conclusions) have been removed. Also, we have re-written some part of the text from the table to show relevant information only. We now think that this table is more concise with these changes.

 

Additional suggestions:

Comment: 6). Line 34, reformulate ‘other mechanisms are different’.

Reply: We have replaced the sentence by “However, they (referring to M-MDSC and G-MDSC) also use different pathways to carry out immunosuppression. For example…”

 

Comment: 7). Line 52, TME is not defined upon first mention.

Reply: We have included “… tumor microenvironment (TME)” in the first mention.

 

Comment: 8). Line 59, what does ‘it’ refer to? ‘Deficit of nutrient’? Be correct, maybe use ‘nutrient deficiency’ instead?

Reply: We have rewritten the sentence as “… the presence or deficit of some nutrients may have effects on inflammation (1) and, consequently, in cancer and MDSC”, to avoid the “it” mentioned by the reviewer.

 

Comment: 9). Line 87, define ‘Treg’

Reply: ‘Treg’ was already defined in its first mention (lines 46-47), in the sentence “…together with other immunosuppressor cells such as regulatory T cells (Treg), or M2 macrophages (2)”.

 

Comment: 10). Line 88, reformulate ‘also have influenced’

Reply: We have rewritten the sentences as “In addition, the active form of vitamin D (1,25(OH)2D) plays a role in the regulation of MDSC…”.

 

Comment: 11). Line 94, reformulate ‘on oncological settings’

Reply: We have rewritten the sentences as “Therefore, we aimed to assess a scoping review to discuss how nutrients could modulate MDSC in cancer”.

 

Comment: 12). Line 240, reformulate ‘also lead MDSC development’

Reply: We have rewritten the sentences as “…which also promote the proliferation and accumulation of MDSC within the TME”.

 

Comment: 13). Line 242, specify and be more clear ‘some food components’

Reply: We have replaced “some food components” by “nutrients”.

 

Comment: 14). Lines 273/274: ‘Importantly, the studies evaluated in this review also analyzed other cells involved in the tumor mechanisms, such as Tregs, CD8+ T cells, or NK cells.’ while that might be true, it is better to devote some more writing to the explanation on these classes of cells (see also point 8) as this is might not be familiar to the general reader, and make this issue a sub result of this scoping review, giving the paper more weight.

Reply: In this sentence, we have included a brief explanation that could be helpful for the general reader. Now, the sentence is “Importantly, the studies evaluated in this review also analyzed other cells involved in the tumor mechanisms, such as Tregs, with immunosuppressive functions, as well as other type of cells with potent cytotoxic antitumor response, such as CD8+ T, or NK cells”.

 

Comment: 15). Line 306, reformulate ‘it has been shown a relationship’

Reply: We have rewritten the sentences as “The intake of soy isoflavones has been related in Asian countries with a lower risk of developing hormone-dependent tumors and a better prognosis (3, 4)”.

 

Round 2

Reviewer 2 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

The authors did an excellent job in upgrading this review. I only hope that the current Table 1. Description of the 7 selected articles will be part of the main article, and not a supplementary table.

Author Response

Comment: The authors did an excellent job in upgrading this review. I only hope that the current Table 1. Description of the 7 selected articles will be part of the main article, and not a supplementary table.

Reply: Thank you for positively evaluating the work done to improve this review. We have removed Table 1 from the supplementary material and have placed it in the main text after its first mention (line 151).

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

Comments and Suggestions for Authors

Myeloid-derived suppressor cells (MDSC) are linked to cancer progression, affecting immune response and aiding tumor growth and metastasis. Certain nutrients can impact MDSC activity, potentially altering cancer prognosis and treatment outcomes, especially in immunotherapy. The study examines how specific dietary patterns and nutrients, like selected vegetables and vitamins, may affect MDSC and cancer development. A qualitative scoping review method is used, focusing on recent studies (2015-2022) that explore the relationship between nutrients, MDSC, and cancer. The study suggests that EGCG reduces the immunosuppressive capacity of MDSCs by inhibiting the Arg1 metabolic route and reducing the production of reactive oxygen species (ROS), among other effects. It highlights the role of diet as a protective or risk factor in cancer development, noting the lower incidence of prostate cancer in Asian countries, potentially due to dietary differences. The paper discusses how certain nutrients affect MDSC proliferation, differentiation, and immunosuppressive capacity, which can be direct or indirect by regulating biomarkers. The text details the relationship between vitamin D and cancer, emphasizing its anti-proliferative, pro-apoptotic, and pro-autophagic effects on tumor cells, as well as its role in reducing systemic inflammation and antioxidant effects. Specific comments:

1.          The paper discusses the role of myeloid-derived suppressor cells (MDSC) in cancer, particularly their immunosuppressive function. It would be beneficial to clarify how MDSC differentiation is influenced by various nutrients.

2.          The paper mentions that certain nutrients can modify chronic inflammation through interaction with MDSC. Can you provide more detailed mechanisms of how these nutrients exert their influence?

3.          The scoping review aims to evaluate the influence of nutrients on MDSC in cancer immunotherapy. How comprehensive is the literature search in covering all relevant studies?

4.          The paper references the Mediterranean diet’s protective effects against certain cancers. Could you expand on other dietary patterns that might have similar protective roles?

5.          The paper presents findings from animal models and pre-clinical trials. How can these results be translated to human clinical practice?

6.          The conclusion suggests nutrient supplementation can reduce MDSC and improve cancer prognosis. Is there evidence to support the efficacy of this approach in clinical trials?

7.          The review suggests combining nutrients with immunotherapies could improve treatment response. Can you discuss potential synergies or conflicts with existing treatments?

8.          The paper calls for more studies on the relationship between nutrients and MDSC. What specific areas of research do you believe are most promising?

9.          Considering individual variability in diet and lifestyle, how can the findings be applied in a real-world clinical setting to benefit patients with cancer?

 

 

Author Response

I am trying to withdraw the manuscript

Reviewer 2 Report

Comments and Suggestions for Authors

Although the objective is worth preparing a review for, the execution and presentation of the review is not done according to scientific standards, meaning that integrated academic writing and additional presentation of the tabulated identified papers is required. It is suggested to minimally add subheaders in the results section while transferring supplementary Table 2 to the main paper.

Sections with lines 74/77 and 111/118 both hold reasons to perform this review, with again repeated in section 2. Especially the latter is a poor way of explaining the objectives and should be integrated into the introductory sections.

Section 3 should be written up as a scientific methods section, and it is not completely clear why the research strategy is repeated in supplementary table 1. All tabulated parameters are part of the methods section, so table 1 is redundant, even the number of documents of Table 1 as they should be clear from Figure 1.

The final results for this review are 7 identified papers that are summarized both in supplementary Table 2 and the results section. Table 2 should be used in the main paper, not in the supplements and the results section should properly describe the findings, while giving summarized statement of the paper’s content in the Table. The written text of the results section should more clearly describe the identified papers and integrate the use of the table. Currently both results and discussion are too little scientifically presented, while repeating actual numbers of compared groups with significance levels from the original research papers. Not sure whether this makes complete sense. It would be sounder to describe and actually write the effects observed, not repeat the content of the papers. Results are presented as individual statements, but the review purpose is to prepare a readable and understandable text that comes to answer the objectives.

Many sections in the introduction need references.

Comments on the Quality of English Language

Although the objective is worth preparing a review for, the execution and presentation of the review is not done according to scientific standards, meaning that integrated academic writing and additional presentation of the tabulated identified papers is required. It is suggested to minimally add subheaders in the results section while transferring supplementary Table 2 to the main paper.

Sections with lines 74/77 and 111/118 both hold reasons to perform this review, with again repeated in section 2. Especially the latter is a poor way of explaining the objectives and should be integrated into the introductory sections.

Section 3 should be written up as a scientific methods section, and it is not completely clear why the research strategy is repeated in supplementary table 1. All tabulated parameters are part of the methods section, so table 1 is redundant, even the number of documents of Table 1 as they should be clear from Figure 1.

The final results for this review are 7 identified papers that are summarized both in supplementary Table 2 and the results section. Table 2 should be used in the main paper, not in the supplements and the results section should properly describe the findings, while giving summarized statement of the paper’s content in the Table. The written text of the results section should more clearly describe the identified papers and integrate the use of the table. Currently both results and discussion are too little scientifically presented, while repeating actual numbers of compared groups with significance levels from the original research papers. Not sure whether this makes complete sense. It would be sounder to describe and actually write the effects observed, not repeat the content of the papers. Results are presented as individual statements, but the review purpose is to prepare a readable and understandable text that comes to answer the objectives.

Many sections in the introduction need references.

Specific comments on Abstract and Introduction:

Line 14, specify ‘many diseases’

Line 19 to write as: Thus, from the literature, a significant reduction of cancer growth and progression can be observed’

Line 22 replace ‘which result beneficial’ with ‘, with beneficial results not only for’

Line 39 ‘ MDSC come from the same stem cells as normal myeloid cells’ needs references

Lines 43/44 needs references

Line 48 expand on the difference between granulocytic and monocytic.

Line 49/50 give reference for ‘Even so, M-MDSC appear  to have a greater immunosuppressive capacity.’

Line 53/54: ‘Their’ refers to MDSC in general. Please specify!

Line 53/55 give references for ‘Their presence in the tumor microenvironment is one of the large variety of mechanisms which the tumor trigger to keep unnoticed by the immune system. Nowadays, most part of these mechanisms are still unknown for the scientific community.’

Line 62 ‘In this study, they’ please write differently. Citation is #10. Perhaps repeat Sánchez-Pino et al?

Line 63, ‘anti-PD-1/PD-L1 ‘ please give definition and abbreviation upon first mention. Even though these are common molecules. Same could be said for line 68/69, but at least here is mentioned ‘proinflammatory molecules’

Lines 72/73 needs references ‘M2 macrophages, another subtype of TAM, tend to be immunosuppressive’

Lines 74/77 should be adjusted: ‘Therefore, it is of general interest in the field of MDSC to improve the knowledge and understanding about 1) those factors that benefit the accumulation of MDSC in the tumor microenvironment; 2) those factors that limit the acquisition of their immunosuppressive capacity, is a potential line of investigation towards the development of therapies that prevent the tumor from growing.’

Lines 82/83 give references

Line 84/85 give references ‘These days, it is known that the presence of some or the deficit of other nutrients can have effects on inflammation’

Lines 89/93 need references

Lines 101/104 need references

Line 105 mentions ‘there are studies’ however none are cited.

Lines 107/110 need references

Author Response

I am trying to withdraw the manuscript