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Systemic Adaptive Immune Parameters Associated with Neuroblastoma Outcomes: the Significance of Gamma-Delta T Cells

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Abstract

We mined a set of neuroblastoma (NBL) exomes for immune receptor recombinations representing all seven, human adaptive immune receptor genes, using a very high standard for identifications of V- and J-gene segments in sequencing reads. Results indicated an unusually large number of TRD recombination reads in the NBL samples, possibly related to the younger age of the patients. In general, recovery of immune receptor (IR) recombination reads representing any of the immune receptors, from either blood or tumor samples, was associated with a lower overall survival rate, consistent with an emerging literature indicating that systemic immunology parameters can be informative for cancer evaluations. Despite the overall negative association of IR recombination frequencies and outcomes, survival rate distinctions could still be established as associated with certain chemical features of IR complementarity determining region-3 (CDR3) amino acid sequences, thereby likely revealing a distinction between the negative impacts of a general adaptive immune response versus the positive aspects of specific CDR3 chemical interaction potentials. These data underscore the relevance of gamma-delta T cells in the development of cancer in younger patients. And for the first time, these data allow a distinction within an NBL cohort with active disease, between two contrasting systemic immune states: (i) general and likely harmful adaptive immunity development versus (ii) a likely positive, adaptive immune response with particular antigenic specificities.

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Data Availability

All original NBL data is available via the genomic data commons with NIH, dbGaP application approval; extensive, additional, processed data related to article conclusions appears in the SOM.

Abbreviations

AA:

Amino acid

BCR:

B cell receptor

CDR3:

Complementarity determining region-3

dbGaP:

Database of genotypes and phenotypes

INSS:

International neuroblastoma staging system

IR:

Immune receptor

LGG:

Lower grade glioma

MKI:

Mitosis-karyorrhexis index

NCPR:

Net charge per residue

OS:

Overall survival

SPSS:

Statistical package for the social sciences

THYM:

Thymoma

TCR:

T cell receptor

TARGET:

Therapeutically Applicable Research to Generate Effective Treatments

TCGA:

The cancer genome atlas

TILs:

Tumor infiltrating lymphocytes

WXS:

Whole exome sequence

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Acknowledgements

Authors gratefully acknowledge the contributions of USF research computing, the extensive administrative work of Ms. Corinne Walters related to NIH approvals for data access, and the taxpayers of the State of Florida.

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Authors and Affiliations

  1. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Etienne C. Gozlan, Boris I. Chobrutskiy, Saif Zaman, Michelle Yeagley & George Blanck

  2. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    George Blanck

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  1. Etienne C. Gozlan
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Contributions

ECG conducted the majority of the analyses and worked on all manuscript drafts; BIC wrote and oversaw software use to obtain and characterize the immune receptor recombination reads and assisted with Cox regression analyses; SZ participated in independent validation of survival distinctions; MY contributed independent analyses of CDR3 features; and GB oversaw project development and finalizing manuscript.

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Correspondence to George Blanck.

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NBL data was accessed via George Blanck project approval number 16405, NIH database of genotypes and phenotypes (dbGaP).

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The authors declare that they have no conflict of interest.

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Gozlan, E.C., Chobrutskiy, B.I., Zaman, S. et al. Systemic Adaptive Immune Parameters Associated with Neuroblastoma Outcomes: the Significance of Gamma-Delta T Cells. J Mol Neurosci 71, 2393–2404 (2021). https://doi.org/10.1007/s12031-021-01813-x

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