Breaking the Invisible Barriers: Unleashing the Full Potential of Immune Checkpoint Inhibitors in Oncogene-Driven Lung Adenocarcinoma

Round 1

Reviewer 1 Report

Kwok et al., have submitted a comprehensive and relevant review on the topic of use of immune checkpoint inhibitors for the treatment of oncogene-driven lung adenocarcinoma “Breaking the invisible barriers…”. This review details the current state of our knowledge on the topic of tumor immune microenvironment in lung adenocarcinoma, as well as discussing relevant literature regarding the potential role of oncogenic mutations, and therapies targeting these mutational alterations, in the response to immune checkpoint inhibitors. Overall, this is a comprehensive and well-written review. However, a few issues must be addressed:

1. Several grammatical mistakes/incomplete sentences have been identified, mainly in the abstract and introduction. The entire manuscript should be proofread, and all grammatical errors corrected.

2. Conclusions and future directions contains several concepts that were not introduced or discussed in the manuscript. It is recommended that these concepts be initially described in the appropriate context in the body of the manuscript and then summarized or emphasized for its importance and focus of future research in this section.

An article highlight the role of PKCi in Kras-driven LUAD susceptibility to ICI. It demonstrates efficacy in a preclinical mouse model of LUAD and reveals a correlation of PKCi and patient response to ICI.

Yin et al, Protein kinase Ciota mediates immunosuppression in lung adenocarcinoma. Sci Transl Med 2022 Nov 16;14(671):eabq5931. doi: 10.1126/scitranslmed.abq5931

Some improvement to grammar is necessary. See attached review.

Author Response

Thank you for the valuable comments from the reviewer. We have replied to the reviewer's comments and revised the manuscript accordingly

Kwok et al., have submitted a comprehensive and relevant review on the topic of use of immune checkpoint inhibitors for the treatment of oncogene-driven lung adenocarcinoma “Breaking the invisible barriers…”. This review details the current state of our knowledge on the topic of tumor immune microenvironment in lung adenocarcinoma, as well as discussing relevant literature regarding the potential role of oncogenic mutations, and therapies targeting these mutational alterations, in the response to immune checkpoint inhibitors. Overall, this is a comprehensive and well-written review. However, a few issues must be addressed:

1. Several grammatical mistakes/incomplete sentences have been identified, mainly in the abstract and introduction. The entire manuscript should be proofread, and all grammatical errors corrected.

Reply 1: We have proofread and corrected all the grammatical errors in the revised manuscript.

2. Conclusions and future directions contains several concepts that were not introduced or discussed in the manuscript. It is recommended that these concepts be initially described in the appropriate context in the body of the manuscript and then summarized or emphasized for its importance and focus of future research in this section.

Reply 2: We have added Section 5 “Novel techniques in characterization of tumor immune phenotypes” to further discuss the importance of these techniques in future research.

An article highlight the role of PKCi in Kras-driven LUAD susceptibility to ICI. It demonstrates efficacy in a preclinical mouse model of LUAD and reveals a correlation of PKCi and patient response to ICI.

Yin et al, Protein kinase Ciota mediates immunosuppression in lung adenocarcinoma. Sci Transl Med 2022 Nov 16;14(671):eabq5931. doi: 10.1126/scitranslmed.abq5931

Reply 3: The reference has been added as Ref 107.

Reviewer 2 Report

This a nice manuscript, but the authors may consider these points to improve the current version;

1) genetic background is an important factor in response to lung cancer treatments. The authors should add a new part regarding the role of genetic in lung cancer treatment using the relevant publications such as Zahra Fathi, et al - 2018 and so on

2) There is no data regarding the response to PD-1/ PD-L1 treatment in some population such as west part of Asia. The authors need to add this part to the manuscript using the relevant articles 

3) Adding a relevant figure can help the readers to use the artcile 

Minor typos 

Author Response

Thank you for the valuable comments from the reviewer. We have replied to the reviewer's comments and revised the manuscript accordingly,

This a nice manuscript, but the authors may consider these points to improve the current version;

1) genetic background is an important factor in response to lung cancer treatments. The authors should add a new part regarding the role of genetic in lung cancer treatment using the relevant publications such as Zahra Fathi, et al - 2018 and so on

Reply 1: The reference has been added as Ref 6.

2) There is no data regarding the response to PD-1/ PD-L1 treatment in some population such as west part of Asia. The authors need to add this part to the manuscript using the relevant articles 

Reply 2: We have added further information about the geographical difference in terms of genetic variants and their response to ICIs in the introduction.

3) Adding a relevant figure can help the readers to use the article

Reply 3: Figure 3 was added to summarized the tumor immune microenvironment of EGFR-mutated lung ADC.