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Review
Peer-Review Record

Hypoxia-Driven Immune Escape in the Tumor Microenvironment

by Alyssa Vito 1,†, Nader El-Sayes 1,† and Karen Mossman 2,*
Reviewer 1: Anonymous
Reviewer 2: Anonymous
Reviewer 3:
Submission received: 6 March 2020 / Revised: 5 April 2020 / Accepted: 13 April 2020 / Published: 16 April 2020
(This article belongs to the Special Issue Immunology of Cell Death in Cancer Immunotherapy)

Round 1

Reviewer 1 Report

This review is focusing on the correlation between the theme of hypoxia-driven immune escape and the character of immunogenic cell death (ICD) in the tumor microenvironment (TME). I believe this review enable us to better understand these cross-links between the ability of hypoxia to induce ICD and its potential targets for treatment. Authors have mentioned the immunogenicity in the TME with respect to the correlation between the immune system and cancer. I think this review are worth being accepted to our journal.

Author Response

We thank the reviewer for their positive feedback and for recommending our manuscript for publication.

Reviewer 2 Report

The proposed plan is quite well. Nevertheless, the authors should probably add to be complete a paragraph focusing on the metabolic switch that go further than just glycolysis in tumor cells and in immune cells. In fact, many cancers now are described with their adaptive metabolism involving aminoacids or lipids. 

For the introduction, the authors maybe should add a small part describing briefly the main proteins involved in the hypoxia-related pathways to be more comprehensive. 

Two paragraphs named as follows: "hypoxia and immune system" and 'hypoxia-mediated therapeutic resistance" are particularly long. Each can be potentially subdivided in two subparagraphs. For hypoxia and immune system, we can maybe propose a part focusing on innate immunity in tumors linked to hypoxia (involving at the end macrophage modulators) and another part on acquired immunity. For the therapeutic resistance, maybe it will be less confusing to subdivide it in a part describing the primary and initial tumor resistances and in a second part the acquired resistances after treatment and at relapse. 

In the paragraph 2. talking about immune system, there is no differentiation between DC and cells presenting antigen. It might be clearer to describe them closely. In this part, the authors were also explaining the T cells' (lines from 158 to 176) role, but it is quite confusing. They are mixing together their immunosuppressive and immunostimulatory roles. They should described them differently to add some clarity and explain the main cells and metabolisms involved in each process. 

For the paragraph 3. on cell death, it might be very interesting to also describe the impact of senescence and autophagy as hypoxia-related proteins like mTor are inducing them strongly.

In the therapeutic resistances description, the authors could also add a specific part or put altogether the sentences turning around tumor antigen secretion and production to stimulate T cells during hypoxia. 

Finally, in the immunotherapies, they did not any time outline the mTor inhibitors. In fact, most of them are inhibiting the protein during hypoxia stimulation. Nevertheless, they are also known as inhibitors of T cells' functions. It could be a major and controversial input to this therapeutic part of the review to add a specific item on mTor inhibitors and maybe explore the different roles of mTORC1 and mToRC2 on immune system.

For the english language, some sentences are particularly long and could be shortened. It could add some clarity along the manuscript.

          

Author Response

Reviewer 2:

The proposed plan is quite well. Nevertheless, the authors should probably add to be complete a paragraph focusing on the metabolic switch that go further than just glycolysis in tumor cells and in immune cells. In fact, many cancers now are described with their adaptive metabolism involving aminoacids or lipids. 

For the introduction, the authors maybe should add a small part describing briefly the main proteins involved in the hypoxia-related pathways to be more comprehensive. 

Author’s response: We thank this reviewer for their thorough comments and suggestions in helping to improve this manuscript. We have addressed these comments with the addition of a new section in the review, titled “Hypoxia Signaling and Metabolism”. In this section, the reviewers will find that we have discussed the main proteins involved in the hypoxia-related pathways and gone into more detail with regards to the metabolic switch occurring under hypoxia conditions (Lines 84-147).

Two paragraphs named as follows: "hypoxia and immune system" and 'hypoxia-mediated therapeutic resistance" are particularly long. Each can be potentially subdivided in two subparagraphs. For hypoxia and immune system, we can maybe propose a part focusing on innate immunity in tumors linked to hypoxia (involving at the end macrophage modulators) and another part on acquired immunity. For the therapeutic resistance, maybe it will be less confusing to subdivide it in a part describing the primary and initial tumor resistances and in a second part the acquired resistances after treatment and at relapse. 

Author’s response: We thank the reviewer for this suggestion. For the section “hypoxia and the immune system”, we divided the section based on the effect of hypoxia on specific immune cells (Lines 150-301). This change will make the overall section more approachable. We have also divided “hypoxia-mediated therapeutic resistance” section into two sub-sections, as suggested (Lines 392 and 436).

In the paragraph 2. talking about immune system, there is no differentiation between DC and cells presenting antigen. It might be clearer to describe them closely. In this part, the authors were also explaining the T cells' (lines from 158 to 176) role, but it is quite confusing. They are mixing together their immunosuppressive and immunostimulatory roles. They should described them differently to add some clarity and explain the main cells and metabolisms involved in each process. 

Author’s response: We have added semantic details to clarify the distinction of DCs as being one of many types of antigen-presenting cells. For the sub-section talking about T cells’ role, we have re-organized the section as suggested so that there is more segregation between the immunosuppressive and immunostimulatory roles of this cell type (Lines 165-179 and 230-267 respectively).

For the paragraph 3. on cell death, it might be very interesting to also describe the impact of senescence and autophagy as hypoxia-related proteins like mTor are inducing them strongly.

Author’s response: In the section titled “Hypoxia and Immunogenic Cell Death” we have added in a section discussing mTOR, UPR and autophagy and how this may be linked to both hypoxia and immunogenic cell death (Lines 354-365).

In the therapeutic resistances description, the authors could also add a specific part or put altogether the sentences turning around tumor antigen secretion and production to stimulate T cells during hypoxia. 

Author’s response: We chose to instead address this in the ICD section, as it has been well established that ICD is a process that results in secretion of tumor antigens, which in turn promotes DC-mediated antigen presentation and stimulation of T cell activity (Lines 359-371).

Finally, in the immunotherapies, they did not any time outline the mTor inhibitors. In fact, most of them are inhibiting the protein during hypoxia stimulation. Nevertheless, they are also known as inhibitors of T cells' functions. It could be a major and controversial input to this therapeutic part of the review to add a specific item on mTor inhibitors and maybe explore the different roles of mTORC1 and mToRC2 on immune system.

Author’s response: We thank the reviewer for this suggestion. As per the suggestion we have indeed added in a paragraph discussing mTOR inhibitors as potential immunotherapies and the potential implications of mTOR inhibitors for improving or hampering immunotherapies. You can find this addition in our section titled “Hypoxia-Targeted Immunotherapies” (Lines 506 – 520 and 535 - 539).

For the english language, some sentences are particularly long and could be shortened. It could add some clarity along the manuscript.

Author’s response: We have re-read the manuscript and focused on making sentences succinct and understandable throughout.

Reviewer 3 Report

In the presented manuscript entitled: ”Hypoxia-driven immune escape in the tumor microenvironment,” Vito, with colleagues, aimed to review how low oxygen supply in cancer impact immune anti-cancer cell response.  While correct facts are presented the significance of the study will benefit from a more broad view on the topic i.e.

  • discussion of response of different immune cells to hypoxia (macrophages, NK cells, T cells – each in separate chapters)
  • compare HIF1a vs HIF2A (a.k.a EPAS1) mechanistic difference
  • using more informative cartoons
  • include a table with a specification of cancer-immune cells secretome affected by hypoxia

Author Response

Reviewer 3:

 

In the presented manuscript entitled: “Hypoxia-driven immune escape in the tumor microenvironment,” Vito, with colleagues, aimed to review how low oxygen supply in cancer impact immune anti-cancer cell response. While correct facts are presented the significance of the study will benefit from a more broad view on the topic i.e.

Author’s response: We thank this reviewer for their valuable feedback. We have taken these considerations into account to improve the coverage of topics in the review (a summary of how we addressed specific comments can be found below). We would like to note, however, that this review focuses on the potential of hypoxia to induce immunogenic cell death, resistance mechanisms that can be potentiated by hypoxia, and the implications associated with combining hypoxia-targeted therapies with different forms of immunotherapy.

 

  • discussion of response of different immune cells to hypoxia (macrophages, NK cells, T cells – each in separate chapters)

 

Author’s response: In our section titled “Hypoxia and the Immune System” we added sub-sections outlining how hypoxia effects the maturation, function and activity of different immune cells in the TME. (Lines 150-301)

 

  • compare HIF1a vs HIF2A (a.k.a EPAS1) mechanistic difference

 

Author’s response: In our newly added section titled “Hypoxia Signaling and Metabolism” we have described and compared the roles of HIF-1a and HIF-2a in hypoxic and normoxic conditions, as suggested. (Lines 85-116)         

 

  • using more informative cartoons

 

Author’s response: We have included additional figures and tables throughout and altered the original figures to be more informative. (Fig1: summary of HIF pathway, Fig2: illustration of overlapping and distinct functions of HIF1-α and HIF2-α, Fig 3: adaptations in cancer cell metabolism under hypoxic conditions, Fig 4: Immunotherapy resistance mechanisms driven by hypoxia).

 

  • include a table with a specification of cancer-immune cells secretome affected by hypoxia

 

Author’s response: We like this suggestion and think it would make for an excellent summary of our section focused on how hypoxia changes immune cell phenotypes. To address this comment, we have added a table (table1) listing hypoxia-mediated changes in immune-cell functions and secretome.

Round 2

Reviewer 2 Report

I am pleased with all corrections affording by the authors. it is now suitable for publications. 

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