Abstract 2891: Landscape of infiltrating immune repertoire in pediatric solid tumors
Authors: Nabbi Arash , Jäger Natalie , Sudhaman Sumedha , Sun Pengbo , Yang S. Y. Cindy , Zhu Kelsey , Kool Marcel , Rathi Komal , Kalletla Karthik , Raman Pichai , Zhu Yuankun , Paulson Joseph N. , Jones David T. , Tabori Uri , Resnick Adam C. , Pfister Stefan M. , Pugh Trevor J. 
Published: August 2019

Abstract
Introduction: Immune repertoire is a highly diverse pool of B and T cell receptors (B/TCR) that determine boundaries of immune surveillance. Pre-existing immune clones within Tumor MicroEnvironment (TME) suggest existence of a functional antigen presenting machinery and recognizing T cells, which fail to eliminate tumor, likely due to immunosuppressive environment. Shifts in composition of immune repertoire upon immune checkpoint blockade have been reported in adult cancers and shown to be associated with clinical response. As immunotherapy is being introduced to pediatric oncology, there is a need to better understand immunogenomic aspects of TME in childhood cancers.
Objective: We hypothesize that characteristics of TCRs in conjunction with gene expression profile of immune cells are key determinants of immune response in pediatric patients.
Methods: We compiled a pan-pediatric cohort and associated RNAseq datasets through multiple research initiatives. Participating programs include NCI TARGET (n ~ 270), International Cancer Genome Consortium (ICGC, n ~ 250) and Children’s Brain Tumor Tissue Consortium (CBTTC, n ~ 790). As comparator, we analyzed 7 adult cancer types as well as data from constitutive mismatch repair deficiency (CMMRD) consortium. We devised a simple and reliable index to estimate immune diversity. We used CIBERSORT tool to infer immune fraction of TME and investigated immune-related gene expression. In partnership with Gabriela Miller’s Kids First Data Resource Centre, analyses were performed on CAVATICA computational platform.
Results: While median number of RNAseq reads were comparable across TARGET, CBTTC and TCGA datasets (~ 67-90 million reads), ICGC dataset contained a median of ~ 208 million reads. However, number of reads mapped to immune loci were comparable across all datasets and appeared to be confounded by infiltration extent rather than technical discordance. Our preliminary results indicate Neuroblastoma harbored the highest median of inferred diversity across pediatric cancers (TRβ=59.38). Inferred immune content indicated a range of infiltration from 0.59 in Teratoma/Germinoma to 0.15 in Medulloblastoma. Immune checkpoint gene expression across pediatric cancers show overall downward trend compared to adult counterparts.
Conclusions: Our comprehensive study will serve as a common ground for researchers to delineate immune component of pediatric tumor microenvironment. Covered in this study are common solid tumors as well as rare malignancies, characterization of which will aid rational design of immunotherapy-related clinical trials of pediatric cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Arash Nabbi, Natalie Jäger, Sumedha Sudhaman, Pengbo Sun, S. Y. Cindy Yang, Kelsey Zhu, Marcel Kool, Komal Rathi, Karthik Kalletla, Pichai Raman, Yuankun Zhu, Joseph N. Paulson, David T. Jones, Uri Tabori, Adam C. Resnick, Stefan M. Pfister, Trevor J. Pugh. Landscape of infiltrating immune repertoire in pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2891.