Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma

Abstract

Neuroblastoma grows within an intricate network of different cell types including epithelial, stromal and immune cells. The presence of tumor-infiltrating T cells is considered an important prognostic indicator in many cancers, but the role of these cells in neuroblastoma remains to be elucidated. Herein, we examined the relationship between the type, density and organization of infiltrating T cells and clinical outcome within a large collection of neuroblastoma samples by quantitative analysis of immunohistochemical staining. We found that infiltrating T cells have a prognostic value greater than, and independent of, the criteria currently used to stage neuroblastoma. A variable in situ structural organization and different concurrent infiltration of T-cell subsets were detected in tumors with various outcomes. Low-risk neuroblastomas were characterized by a higher number of proliferating T cells and a more structured T-cell organization, which was gradually lost in tumors with poor prognosis. We defined an immunoscore based on the presence of CD3⁺, CD4⁺ and CD8⁺ infiltrating T cells that associates with favorable clinical outcome in MYCN-amplified tumors, improving patient survival when combined with the v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) status. These findings support the hypothesis that infiltrating T cells influence the behavior of neuroblastoma and might be of clinical importance for the treatment of patients.

Keywords:

• clinical outcome
• correlation network analysis
• neuroblastoma
• prognostic marker
• T cells
• tumor-infiltrating T lymphocytes

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank A. Alisi, G. Jurman and M. Rosado for critical reading of the manuscript.

Funding

This work was supported by Italian Ministry of Health (Rome, Italy) grant PE-2011-02351866 (DF) and the Special Project “5 × 1000” Associazione Italiana per la Ricerca sul Cancro (AIRC, Milan, Italy) grant 9962 (FL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation on the manuscript.

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