The Prognostic and Predictive Significance of Tumor-Infiltrating Memory T Cells Is Reversed in High-Risk HNSCC
, Maike Büttner-Herold 2,3, Christoph Daniel 2,3, Arndt Hartmann 2,4, Rainer Fietkau 1,2 and Luitpold Distel 1,2,*
Round 1
Reviewer 1 Report
Hartan et al submitted a paper titled " The prognostic significance of tumor-infiltrating memory T cells is reversed in high-risk HNSCC". The author summarizes the prognostic value of CD45RO in HNSCC.The author provides a well-organized article to identify the importance of CD45RO in low-risk and high-risk HNSCC patients. But the author can improve this manuscript for better understanding.
General comments
1. According to the method, the TMA samples were treatment-naive tissues or biopies. As shown in Table 1, different treatment strategies were used such as RCT (radiochemotherapy), OP+adjuvant RCT and Neoadjuvant RCT+OP. The role of CD45RO may have different prognostic value in different treatments, The author should stratify into three subgroups to compare the impact of CD45RO.
2. Due to tumor heterogenity, the spot location may influence the results. Did author take two spots from the same patients to avoid this issue?
Author Response
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Author Response File: 
Author Response.pdf
Reviewer 2 Report
In the present study, the authors investigated the long-term prognostic relevance of CD45RO+ memory T cells in the clinical characteristics of HNSCC. The present study showed that high CD45RO+ cell densities were clearly associated with prolonged overall survival, recurrence-free interval as well as no evidence of disease status after 10 years. In contrast, the prognostic significance of tumor-infiltrating memory T cells was completely reversed in high-risk groups. I think that topic and obtained results of this study is interesting. However, there are several flaws in this manuscript. The most issue that I feel is that this manuscript is not deeply associated with Radiation though this manuscript is submitted to the Special Issue “Cancer and Radiation Therapy”. The authors have to describe the relationship between this study and Radiation
Comments:
1. Table 1: The authors have to add the foot note of table. For example, full name of some abbreviation such as CRT is missing.
2. Is the type of treatment associated with the clinical characteristics of HNSCC? Similarly, is the type of treatment associated with CD45RO+ T cell densities？
3. Figure 1E-K: Figures and the fonts in the Figure is too small. The authors have to revise them.
Author Response
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Author Response File: Author Response.pdf
Reviewer 3 Report
The manuscript shows interesting outcomes and there are several things to consider.
The use of the term ‘prognostic’ seems not appropriate, and the term ‘predictive’ might be more appropriate. Because the survival outcomes of grade or lymph node involvement are dependent on the CD45RO+ cell density. That is, for example, in Fig. 3, patients with low grade have better OS when the cell density is high, while those with high grade have worse OS when the cell density is high.
Secondly, in Fig. 3, please also perform the interaction analysis between CD45RO+ cell density and grade and between CD45RO+ cell density and lymph node involvement over survival outcomes.
Thirdly, since the patient demographics are available, it would be also great if the authors show the survival outcomes after adjusting at least for age and gender.
Other comments
The term ‘recurrence-free survival (RFS)’ will be more appropriate than ‘recurrence-free interval (RFI).’
For survival curves, please provide also hazard ratio (HR) and its 95% CI as well as median OR/RFS/no-evidence-of-disease and 95% CI.
In Table 1, for age, please provide SD as well as median and range.
Author Response
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Author Response File: Author Response.pdf
Reviewer 4 Report
The manuscript entitled "The prognostic significance of tumor infiltrating memory T cells is reversed in high risk HNSCC" ny Hartan et al. is a very well written and described study. This study shows that CD45RO+ cell density is a potential biomarker that can be used as prognostic purpose. Although the abundance level of this marker shows positive prognostic value however it depends on the disease stage and histological grade.
Overall this study is just one of the beginning of evaluating these markers and further characteristics is required to complete it. There is a major question can this marker (CD45RO+) can be compared with its counter part such as CD45RA+ cell densities to evaluate the prognostic value ? Also just CD45RO+ cells population have heterogeneity in itself such as different memory phenotype and also TRegs population express CD45RO+ marker. Can authors throw some light one the different memory subtype and its correlation with the disease prognostic value. I think some part in the discussions are to be properly added to highlight the importance of individual population that is represented in CD45RO+ heterogeneous population.
Author Response
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Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Thank you for responding to my comments.
I am satisfied with the authors' response.
