Clinical Relevance of CD4 Cytotoxic T Cells in High-Risk Neuroblastoma.

Xao X Tang,Hiroyuki Shimada,Naohiko Ikegaki

doi:10.3389/fimmu.2021.650427

Abstract

Neuroblastoma is the most common extracranial childhood solid tumor. The majority of high-risk neuroblastoma is resistant/refractory to the current high intensity therapy, and the survival of these patients remains poor for the last three decades. To effectively treat these extremely unfavorable neuroblastomas, innovative immunotherapy approaches would be the most promising. In this article, we discuss the identity of tumor-infiltrating effector cells and immunosuppressive cells in high-risk neuroblastoma. Neuroblastoma is unique in that it expresses little or no classical HLA Class I and II. In contrast, high-risk neuroblastomas express the stress-responsive non-classical Class I, HLA-E molecule. HLA-E is the ligand of activating receptors NKG2C/E that are expressed on memory NK cells, CD8+T cells and CD4 CTLs. By examining a comprehensive RNA-seq gene expression dataset, we detected relatively high levels of CD4 expression in high-risk neuroblastoma tissues. The majority of CD4+ cells were CD3+, and thus they were likely tumor-associated CD4+T cells. In addition, high-level of both CD4 and NKG2C/E expression was associated with prolonged survival of the high-risk neuroblastoma patients, but CD8 levels were not, further suggesting that the CD4+ NKG2C/E+ T cells or CD4 CTL conferred cytotoxicity against the neuroblastoma cells. However, this T cell mediated- “protective effect” declined over time, in part due to the progressive formation of immunosuppressive tumor microenvironment. These observations suggest that to improve survival of high-risk neuroblastoma patients, it is essential to gain insights into how to enhance CD4 CTL cytotoxicity and control the immunosuppressive tumor microenvironment during the course of the disease.

Highlights

Neuroblastoma is the most common extracranial childhood solid tumor and is known for its biological and clinical heterogeneity
The expression levels of TGFB1, CXCL12, and CCL2 were highly correlative to each other in all the tumors specimens (Figure S3D). These observations suggest that the production of these cytokines and chemokines by neuroblastoma and cells in the tumor microenvironment (TME) likely determines the quantity of M2 tumor-associated macrophages (TAMs) and M-Myeloid-derived suppressor cells (MDSCs) in highrisk neuroblastoma
Our analysis suggests the roles of M2 TAMs, MDSCs, Treg, and T cell exhaustion in high-risk neuroblastoma in promoting tumor progression

Summary

INTRODUCTION

Neuroblastoma is the most common extracranial childhood solid tumor and is known for its biological and clinical heterogeneity. A previous report suggests that CADM1 is a candidate of tumor suppressors for neuroblastoma at the chromosome 11q23 [56], and the patients with tumors having lost CADM1 expression on cell surface have poor prognosis [56] These observations are consistent with our hypothesis that CRTAM is an important receptor on the effector cell against high-risk neuroblastoma. Levels of TGFB1, CXCL12, and CCL2 were highly correlative to each other in all the tumors specimens (Figure S3D) Taken together, these observations suggest that the production of these cytokines and chemokines by neuroblastoma and cells in the TME likely determines the quantity of M2 TAMs and M-MDSCs in highrisk neuroblastoma. The results suggest that the HLA-E reactive CD4 CTL effector cells are functionally compromised in the TME of high-risk neuroblastoma

DISCUSSION

Findings

DATA AVAILABILITY STATEMENT