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Clinically Relevant Cytotoxic Immune Cell Signatures and Clonal Expansion of T-Cell Receptors in High-Risk

Jun S Wei1, Igor B Kuznetsov2, Shile Zhang1

  • 1Oncogenomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 23, 2018
PubMed

Insights

High-risk neuroblastoma patients with MYCN-NA tumors and high cytotoxic tumor-infiltrating lymphocytes (TIL) signatures show improved outcomes. These findings suggest potential benefits from incorporating immunotherapies into treatment strategies for this patient group.

Area of Science:

  • Oncology
  • Immunology
  • Genomics

Background:

  • High-risk neuroblastoma is an aggressive pediatric cancer with limited therapeutic options due to a low mutation burden.
  • Understanding the tumor microenvironment, particularly tumor-infiltrating lymphocytes (TILs), is crucial for developing novel therapies.

Purpose of the Study:

  • To investigate the biological landscape of high-risk neuroblastoma using RNA sequencing (RNA-seq).
  • To analyze the role and impact of TILs in neuroblastoma, focusing on MYCN-amplified versus MYCN-not-amplified tumors.

Main Methods:

  • Deep RNA sequencing was performed on diagnostic tumors from 129 high-risk and 21 lower-risk neuroblastoma patients.
  • Single-sample gene set enrichment analysis was used to identify TIL gene expression signatures.
  • Associations between TIL signatures, clinical parameters, molecular features, and patient outcomes were examined, with validation in additional cohorts.

Main Results:

  • MYCN-not-amplified (MYCN-NA) neuroblastomas exhibited significantly higher cytotoxic TIL signatures compared to MYCN-amplified (MYCN-A) tumors.
  • A subgroup of high-risk MYCN-NA patients with elevated activated natural killer (NK) cells, CD8+ T cells, and cytolytic signatures demonstrated improved outcomes.
  • Upregulation of immune exhaustion markers indicated an immune-suppressive tumor microenvironment.

Conclusions:

  • RNA signatures of cytotoxic TILs correlate with activated NK/T cells and better outcomes in high-risk MYCN-NA neuroblastoma.
  • These findings suggest that high-risk MYCN-NA neuroblastoma patients may benefit from immunotherapy integration into current treatment regimens.

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