Molecular Targets for Cannabinoids in Natural Killer Cells: Do They Modulate the Antitumor Activity?

Round 1

Reviewer 1 Report

In this review the authors focused on the expression of the endocannabinoid system in NK cells and on the the biological effects of cannabinoids on NK cells. Publications on the effects of cannabinoids on immune cells accumulated over the years but information on the effects on NK cells are limited. In this review the authors selected and reported data specifically on the interplay between cannabinoids and NK cells. 

The review is very  interesting since it summarizes the knowledge on the effects of cannabinoids on NK cell viability, proliferation, migration, cytokine production, and anticancer activity. 

 I find the paper timely considering that the use of cannabinoids is growing in interest as pharmacological anticancer approch. 

The reference section should be improved as suggested.

Line 135-136. Correct the sentence since CB2 has been first identified in immune cells not in the brain. 

I suggest to add some references on FAAH at line 425, as reported below:

1.     https://doi.org/10.1073/pnas.161191698

2.     https://dx.doi.org/10.1007/s00018-012-1074-6

3.     https://doi.org/10.1038/s41467-023-38750-9

4.     https://doi.org/10.1006/cimm.2002.1886.

And at Line 509-510 please add some articles (not only review) as suggested here:

1.      doi: 10.3390/ijms21010025.

2.     Doi: 10.3390/ph14111169

Only minor revision of english are required

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

I found the subject of the review by Olivas-Aguirre to be very interesting and it definitely fills a void in the cannabinoid field.  The information around NK cells is very well presented and it is clear that is the area that the authors are most familiar with.  The first half of the manuscript suffers from poor writing and numerous mistakes.

1. The section from lines 60-78 is difficult to read and it is entirely unclear what the overall message of this paragraph is.  This section needs to be rewritten entirely.  

2. Section 2 on cannabinoids is not only not well written and easily understandable, but also contains numerous mistakes.  For example, the opening sentences implies that cannabinoids produced in plants are related to those produced in animals.  While the molecules share similar activity within the human body, chemically and structurally they are completely unrelated.  This section needs to be entirely rewritten.  Additionally, the quality of the figure in this section is very poor and the double bonds do not visible.

3. Section 3, again this section needs to be entirely rewritten and is fully of errors.  For example, CB2 was discovered on immune cells not in the brain (Munro 1993).   The use of CT to refer to cannabinoid targets is not something typically used in cannabinoid literature and makes for confusing reading.  I think the authors tried to cover too much in this section and it should be reduced in size, refocused on the major targets of cannabinoids.

4. The importance of CYPs in NK cells remains unclear, as it has been reported that nearly all metabolism of cannabinoids occurs via liver enzymes.

Overall, my recommendation would be to find a cannabinoid specialist to help you with the cannabinoid and receptor sections of your manuscript.  It is clear from the section on NK cells, that immunology appears to be your primary field.  I have no doubt that you have worked with cannabinoids in this area, but the sections on cannabinoids and cannabinoid receptors is not presented well in this review, and there are numerous errors presented.

While the article is well written in places, other areas are very unclear and difficult to follow.  I have mentioned several of these in my overall review, but I think the manuscript would greatly benefit from an expert conducting an English language edit.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

While extensive research has been conducted on various cells within the immune system regarding the regulation of the endocannabinoid system, the expression of cannabinoid receptors, and the impact of endo- or Phyto-cannabinoids on their activity, the NK cell population has been somewhat overlooked. Consequently, a notable gap exists in understanding NK cells' role in this context. This review addresses this knowledge deficit, making it both timely and essential.

The text is distinguished by its informativeness and comprehensiveness, characterized by a well-defined structure. It is articulated in a clear, thoughtful style that ensures ease of comprehension. Furthermore, the authors have thoughtfully included self-explanatory, high-quality figures that provide detailed summaries for each review section, enhancing the overall clarity and accessibility of the content.

One main point - the review lacks a crucial section addressing clinical findings and reports on alterations of NK cell numbers or activation among Cannabis users. Numerous studies highlight differences in NK cells among Cannabis users or HIV patient populations, particularly those consuming cannabis or THC/CBD.

I strongly recommend incorporating such a section to either substantiate and fortify the statements made in the manuscript or challenge them, thereby prompting new clinically relevant inquiries.

In dealing with a timely and occasionally controversial topic, the authors are expected to express their personal points of view and perspectives. As a reader, I find it challenging to discern the review's overarching message. The sections are titled and written, for instance, "The anti-tumor activity of cannabinoids," while the content explains the probable inhibition of NK cells or influence on the tumor microenvironment. Clarifying the authors' viewpoint would enhance the overall coherence and impact of the review.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The manuscript has been improved and can be considered for publication

Reviewer 2 Report

The authors have successfully addressed the majority of my concerns.  The revised manuscript is a marked improvement from the original version.  Figure 1 still remains of poor quality, but I will allow the editorial staff to determine if it is adequate for publication.

Markedly improved and no major issues in current version

Reviewer 3 Report

Good enough for me