Immunogenic Cell Death and Elimination of Immunosuppressive Cells: A Double-Edged Sword of Chemotherapy
Round 1
Reviewer 1 Report
The article: Immunogenic cell death and elimination of immunosuppressive cells: a double-edged sword of chemotherapy, is a review article examining the role of DAMPS and immune suppressive cells in immune therapy. While the subject is interesting following are few suggestions to increase the impact of the work.
Overall while the study mentions a lot of studies describing the release of DAMPS with therapy a brief description of the impact this has on therapy would be significant. There is almost no mention of how the released DAMPS work to induce immunogenicity.
The review reads like a collection of facts from different studies but stops short of making an overall discussion on what the literature collectively suggests.
Almost every section in the review would benefit from an overall conclusion/authors perspective on the controversies in the field for that area, a discussion of strengths and weaknesses and a perspective on what is known and what the field needs to advance into.
While ICD can lead to the release of DAMPs, the simple release of DAMP is not synonymous with ICD as necroptic cell death can also release damps in the microenvironment. The authors appear to imply that release of DAMPS always means ICD which is not always true. This should be clarified.
Excessive damp release can also have negative consequences and this should be discussed.
section 2.2 states : “The ICD impact of 5- Fluorouracil (5-FU), a key drug in gastrointestinal cancer, remains debated, with calreticulin exposure [34] and HMGB1 release in some cancer models[35].”
It is not clear what the debate is? Are there other studies that show this is immunosuppressive?? Presumably the release of the mentioned DAMPS increases immune responses: has that been shown, are the mentioned studies.
Overall, with the exception of gemcitabine, antimetabolites appear to be interesting ICD inducers in many models. Please elucidate what interesting refers to here.
Section 2.3: The author’s state: “There are few data concerning topoisomerase 1 inhibitors.” And then go on to cursively mention one study that reports HMGB1 release.
The study should include a section on utility as well as dangers of excessive DAMP release with oncolytic viruses.
Author Response
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Author Response.docx
Reviewer 2 Report
I complement the authors of this excellent review of current information regarding chemotherapy and tumor immunogenicity. The manuscript provides excellent information for those planning or evaluating combination chemotherapy/immunotherapy regimens.
It should be noted that radiation therapy is an important element in the treatment in many of the diseases mentioned. In this light, it would be good to briefly mention the possible contribution of radiation-induced immunogenicity. One such review is as follows:
Ko EC, Benjamin KT, Formenti SC. Generating antitumor immunity by targeted radiation therapy: Role of dose and fractionation. Adv Radiat Oncol. 2018;3(4):486-493.
Author Response
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Reviewer 3 Report
This manuscript is a nice review of the literature as it pertains to the effects of chemotherapy on the immunogenicity of a cancer and the effects on the immunosuppression that cancers induce in their microenvironment. It is well written and well referenced.
I would like the authors to discuss in their reply the choice of the phrase "a double-edged sword of chemotherapy", in the title of this review. This phrase is usually used when we want to convey that something has both a desired and as well an undesired effect. The review mainly discusses the favorable effects [namely immunogenic cell death and depletion of suppressive cells]. Did the authors plan to discuss possible unfavorable effects of chemotherapy as well in the setting of immunotherapy/chemotherapy combinations (the other edge of the sword)? Do we know a lot about the possible detrimental effects of chemotherapy on the desired immune response?
Thank you
Author Response
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Reviewer 4 Report
The authors have written a good review of evidence and make a cogent case for I/O combos. However the article needs balance because several I/O combos have not been positive. Granted the published data is not yet out on a few .
For RCC , in addition to reference 83, would include pembrolizumab+axitinib rini et al , NEJM 2019. Pem+axi was much superior to sutent alone and the synergism is thought to atleast be partially derived from MDSC targeting.
[Update on Phase III DANUBE trial for Imfinzi and tremelimumab in unresectable, Stage IV bladder cancer [news release]. Wilmington, DE: AstraZeneca; March 6, 2020. https://bit.ly/2THDTAm. Accessed March 6, 2020.
Roche provides an update on phase III study of Tecentriq in people with muscle-invasive urothelial cancer [news release]. Basel: Roche; January 24, 2020. https://bit.ly/38zdRoE. Accessed January 24, 2020]
overall this is a instructional and well written review.
Author Response
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Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
The authors have addressed my concerns.
