Immune Checkpoint-Associated Locations of Diffuse Gliomas Comparing Pediatric With Adult Patients Based on Voxel-Wise Analysis
Authors: Li Zhang
Zhangqi Dou
Biao Jiang
Yasaman Iranmanesh
Buyi Zhang
Chongran Sun
Jiawei Wu
Jianmin Zhang
Journal: Frontiers in Immunology (2021)
Discipline: IMMUNOLOGY
Keywords: B7-H3; CD47; PD-L1; immune checkpoint molecules; immunotherapy

Abstract:  Objective: Pediatric diffuse gliomas (pDGs) are relatively rare and molecularly distinct from pediatric pilocytic astrocytoma and adult DGs. Immunotherapy is a promising therapeutic strategy, requiring a deep understanding of tumor immune profiles. The spatial locations of brain tumors might be related to the molecular profiles. We aimed to analyze the relationship between the immune checkpoint molecules with the locations of DGs comparing pediatric with adult patients. Method: We studied 20 pDGs patients (age ≤ 21 years old), and 20 paired adult patients according to gender and histological types selected from 641 adult patients with DGs. Immune checkpoint molecules including B7-H3, CD47, and PD-L1, as well as tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), were manifested by immunohistochemical staining. Expression difference analyses and Spearman's correlation were performed. MRI data were voxel-wise normalized, segmented, and analyzed by Fisher's exact test to construct the tumor frequency and p value heatmaps. Survival analyses were conducted by Log-rank tests. Result: The median age of pediatric patients was 16 years. 55% and 30% of patients were WHO II and III grades, respectively. The left frontal lobe and right cerebellum were the statistically significant locations for pDGs, while the anterior horn of ventricles for adult DGs. A potential association between the expression of PD-L1 and TAMs was found in pDGs (p = 0.002, R = 0.670). The right posterior external capsule and the lateral side of the anterior horn of the left ventricle were predominant locations for the adult patients with high expression of B7-H3 and low expression of PD-L1 compared to pediatric ones, respectively. Pediatric patients showed significantly improved overall survival compared with adults. The prognostic roles of immune checkpoint molecules and TILs/TAMs were not significantly different between the two groups. Conclusion: Immune checkpoint-associated locations of diffuse gliomas comparing pediatric with adult patients could be helpful for the immunotherapy decisions and design of clinical trials. 

Retracted: No

PubPeer comments:
 Dear authors, Fig.1 is quite an eye catcher. I noticed that most of the 4  skulls but not the  tumor frequency signal in each line of the the pediatric and adult group appear similar. This is the case for all views. Could you explain this please? To me it is counterintuitive to see a child skull in the adult group? Thank you! ![file] , 
 Dear reader, Thanks for your contact. As you mentioned, the  4 skulls in each line of the pediatric and adult groups are same. This is because the  skull we used is the MNI152 standard brain template (Montreal Neurological Institute), which do not represent the skull of any specific patient or the average property of all patients. Though it is the fact that the skull shape is different between pediatric and adult ones, the tumor frequency signal still can be overlapped onto the MNI template based on the SPM (Statistical Parametric Mapping) algorithm. If there were other problems, please let us know. We appreciate it again. Regards, Biao Jiang, Chongran Sun, and Jianmin Zhang The Second Affiliated Hospital of Zhejiang University , 
 #2 Dear authors, Thank you very much for the detailed explanation. Now I understand the figure! ,