Age related defects in NK cell immunity revealed by deep immune profiling of pediatric cancer patients
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Abstract
Systemic immunity plays an important role in cancer immune surveillance and therapy but there is little detailed knowledge about the immune status of healthy children or children with cancer. We performed a high dimensional single cell analysis of systemic immunity in pediatric cancer patients and age-matched healthy children. In young children with cancer (age < 8years) NK cells were decreased in frequency, maturity, expression of perforin and granzyme-B, and were less cytotoxic in ex vivo assays. NK cell activity was restored after in vitro culture with interleukin-2. In contrast, older children with cancer (>8 years old) had decreased naive CD4 and CD8 T-cells with concomitant increases in effector memory and T effector memory RA-revertant (TEMRA) T-cells. These immunological changes in pediatric cancer patients are relevant to the better understanding of how cancers diagnosed in childhood interact with systemic immunity and could inform the development and application of effective immune-modulating therapies in the pediatric population.
One Sentence Summary
High dimensional analysis of systemic immunity in pediatric cancer patients reveals clinically relevant immune changes in NK and T-cells that vary with patient age.
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###Reviewer #2:
In this paper, the authors mainly tested peripheral blood mononuclear cells (PBMCs) samples from pediatric cancer and healthy patients by CyTOF, and analyzed the phenotypes of NK, T cells and monocytes. Some scientists have reported these related phenotypes. There is a lack of mechanistic research and many of the conclusions are not yet supported by presented data.
Specific concerns:
The authors collected pediatric cancer samples including hepatoblastoma, neuroblastoma, wilms tumor, lymphoma and et al. These types of tumors are quite different. Whether it's appropriate to analyze together? Lymphoma is a disease of the blood system unlike any other types of tumors. Their systemic immunity must have changed.
No statistical analysis was performed in Fig2D and E. The conclusion of " Classical monocytes are enriched in …
###Reviewer #2:
In this paper, the authors mainly tested peripheral blood mononuclear cells (PBMCs) samples from pediatric cancer and healthy patients by CyTOF, and analyzed the phenotypes of NK, T cells and monocytes. Some scientists have reported these related phenotypes. There is a lack of mechanistic research and many of the conclusions are not yet supported by presented data.
Specific concerns:
The authors collected pediatric cancer samples including hepatoblastoma, neuroblastoma, wilms tumor, lymphoma and et al. These types of tumors are quite different. Whether it's appropriate to analyze together? Lymphoma is a disease of the blood system unlike any other types of tumors. Their systemic immunity must have changed.
No statistical analysis was performed in Fig2D and E. The conclusion of " Classical monocytes are enriched in pediatric cancer patients" is not supported.
Figure 3a is different from the conventional diagram. It was a surprise to see that it showed CD56-dim CD16- and CD56-CD16+ NK cells.
Figure 4 lacks statistical analysis.
Figure 7 lacks correlation analysis. The conclusion of "Pediatric cancer associated immune perturbations vary by age " is not supported. In addition, the presented correlation diagram is insufficient to prove the above conclusion and title.
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###Reviewer #1:
The immune status of pediatric cancer patients may differ from that of adult cancer patients and healthy children. Unraveling the distinct immunological features of pediatric cancers may provide novel therapeutic strategies. Dr. Murali Krishna and colleagues analyzed the composition and phenotype of peripheral immune cells in both pediatric cancer patients and age-matched healthy individuals, and they found some interesting alternations in NK cells, monocytes, and T cell subsets. In general, this descriptive study can be potentially interesting for clinicians, immunologists and cancer researchers. However, several major points remain to be addressed.
The incidence of hematologic tumors is relatively high in children. It is shown in supplemental table 2 that pediatric patients bearing solid tumor and hematologic …
###Reviewer #1:
The immune status of pediatric cancer patients may differ from that of adult cancer patients and healthy children. Unraveling the distinct immunological features of pediatric cancers may provide novel therapeutic strategies. Dr. Murali Krishna and colleagues analyzed the composition and phenotype of peripheral immune cells in both pediatric cancer patients and age-matched healthy individuals, and they found some interesting alternations in NK cells, monocytes, and T cell subsets. In general, this descriptive study can be potentially interesting for clinicians, immunologists and cancer researchers. However, several major points remain to be addressed.
The incidence of hematologic tumors is relatively high in children. It is shown in supplemental table 2 that pediatric patients bearing solid tumor and hematologic malignancies were all included in this study. If solid tumors and lymphoma were analyzed separately, in comparison to healthy individuals, will the major conclusions remain the same?
The type, stage, and therapeutic regimens of cancer may affect the landscape of peripheral immune cells. It is not clear whether any of these factors influence the major conclusion. What were the standards to include healthy pediatric individuals as controls in this study?
The authors focused on immune cell-related differences between healthy and tumor-bearing children. To reveal typical immunological features of pediatric cancer patients, it is recommended to perform similar analyses with samples from adult cancer patients, particularly those bearing the same type of cancers.
The authors claimed that the frequency and cytotoxicity of peripheral NK cells were reduced in young pediatric cancer patients, compared with healthy controls, but these parameters returned to normal in older pediatric cancer patients (>8yrs). Can they separately compare young and old patients with age-matched controls?
The authors believe that diminished killing of tumor cells by NK cells from pediatric cancer patients was due to decreased cytotoxic capacity, rather than inefficient recognition or degranulation. More experimental evidence is needed to substantiate this conclusion. These NK cells were significantly shifted to an immunosuppressive/tolerant pattern (high in PD-1, NKG2A, but low in perforin and Granzyme-B), while Long-term (14 days) stimulation with IL-2 can improve their cytotoxicity. Can short-term IL-2 treatment achieve similar effects (e.g. increased cytotoxicity, elevated expression of lytic molecules and CD57)? Since the frequency and cytotoxicity of NK cells in older pediatric cancer patients (>8yrs) were actually similar to that in normal children, do serum IL-2 levels increase in older cancer patients?
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##Preprint Review
This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 2 of the manuscript.
###Summary:
Dr Taylor and colleagues aimed to emphasize NK cell-related defects in pediatric cancer patients, in comparison to healthy children. This study was potentially interesting, although it was based on descriptive analyses, lacking mechanistic exploration. In addition, this study included a mixed cohort of pediatric patients bearing tumors of different types, stages, and perhaps distinct therapeutic regimens. Some conclusions were not strongly supported by current experimental evidence. It remains unknown whether …
##Preprint Review
This preprint was reviewed using eLife’s Preprint Review service, which provides public peer reviews of manuscripts posted on bioRxiv for the benefit of the authors, readers, potential readers, and others interested in our assessment of the work. This review applies only to version 2 of the manuscript.
###Summary:
Dr Taylor and colleagues aimed to emphasize NK cell-related defects in pediatric cancer patients, in comparison to healthy children. This study was potentially interesting, although it was based on descriptive analyses, lacking mechanistic exploration. In addition, this study included a mixed cohort of pediatric patients bearing tumors of different types, stages, and perhaps distinct therapeutic regimens. Some conclusions were not strongly supported by current experimental evidence. It remains unknown whether similar differences can be found between adult cancer patients and age-matched healthy individuals. To address all these above points, a large amount of further work will be necessary.
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