How Reliable Are Predictions of CD8⁺ T Cell Epitope Recognition? Lessons for Cancer

Round 1

Reviewer 1 Report

The manuscript describes as a commentary incremental data on the T cell antigen repertoire of individual (single) human peripheral blood cells collected with the long established and very successful Immunospot technology from Cellular Technology. 

The key message is that there is a variety of peptide reactivities in an individual HLA-A virus context, which the authors describe as "aleatory". They conclude that for the quality of the assessment of immune strength (CD8 T-cell effector potential) it is not sufficient to consider the immunostimulatory strength of individual epitopes, but rather a large number of them or - in the case of viruses - ideally all of them. They argue that the Immunospot technology of their company can fill this gap.

This insight is not new and has been published by the group several times elsewhere (e.g. Ref. 10, 14,15). Thus, the scientific novelty is limited.

Apart from that, the ms. is well written (you can see the routine of the authors). The methods and their description as well as the illustration give no cause for criticism. The text may be valuable as a "reminder" for readers of the journal.

Author Response

We are grateful for the reviewer's comments, and appreciate that there are no amendments required by them.

Reviewer 2 Report

In their commentary „How reliable are predictions of CD8+ T cell epitope recognition? Lessons for Cancer.“ the authors provide data for the so-called ImmunoSpot assay to detect rare antigen/peptide-specific CD8+ T cells directly via ex vivo measurements of freshly isolated PBMC. They critically discuss these data in the context of T-cell responses to viral and cancer antigens.

This commentary is well-written, well-structured, appealingly illustrated and provides interesting insights into T-cell responses in general and expected hurdles of analyzing anti-tumor T-cell responses.

Minor issues include:

Line 83: … proteins that are that are …

Line 304: A reference seems to be missing.

Figures: Many vital figures are only shown as supplemental figures.  

Author Response

We are grateful for the reviewer's positive comments. 

The minor comments below have been addressed as follows:

Line 83: … proteins that are that are …  "that are" has been deleted

Line 304: A reference seems to be missing. Reference has been added.

Figures: Many vital figures are only shown as supplemental figures. 

This is because this data has been published by us previously. It can be easily accessed in the supplementary materials section. 

Reviewer 3 Report

The manuscript “How reliable are predictions of CD8+ T cell epitope recognition? Lessons for Cancer” by Lehmann at al argues against the use of restricted number of CD8+ cell epitopes for immune monitoring. In their commentary, authors provided a set of compelling evidences towards the use of systematic agnostic approach with a peptide library, followed by a large scale CD8+ T cell immune monitoring methods such as ELISPOT and ImmunoSpot .

There are some minor comments

1. It may be important to provide at least short notes about the specificity of the large scale ELISPOT and ImmunoSpot assays.

2. Figure S5, “Scenescent” instead of “Senescent” in the Figure.

3. Figure S5 the meaning of color coding of cytokines in that scheme needs to be explained in Figure legend

4. Authors forgotten to find and include a reference, line 303

Author Response

We are grateful for the reviewer's comments. 

We have addressed the comments as below:

1. It may be important to provide at least short notes about the specificity of the large scale ELISPOT and ImmunoSpot assays.                                      Yes, this has been done now.
2. Figure S5, “Scenescent” instead of “Senescent” in the Figure.      Corrected.
3. Figure S5 the meaning of color coding of cytokines in that scheme needs to be explained in Figure legend.     Added. 
4. Authors forgotten to find and include a reference, line 303.    Added.