Immuno-transcriptomic profiling of extracranial pediatric solid malignancies
Andrew S. Brohl, Sivasish Sindiri, Jun S. Wei, David Milewski, Hsien-Chao Chou, Young Song, Xinyu Wen, Jeetendra Kumar, Hue V. Reardon, Uma Mudunuri, Jack Collins, Sushma Nagaraj, Vineela Gangalapudi, Manoj Tyagi, Yuelin J. Zhu, Katherine E. Masih, Marielle E. Yohe, Jack F. Shern, Yue Qi, Udayan Guha, Daniel Catchpoole, Rimas J. Orentas, Igor B. Kuznetsov, Nicolás J. Llosa, John A. Ligon, Brian Turpin, Daniel Leino, Shintaro Iwata, Irene L. Andrulis, Jay S. Wunder, Sílvia Regina Caminada de Toledo, Paul S. Meltzer, Ching C. Lau, Beverly A. Teicher, Heather Magnan, Marc Ladanyi, Javed Khan
Abstract
We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.