The neoepitope landscape in pediatric cancers

Abstract

BackgroundNeoepitopes derived from tumor-specific somatic mutations are promising targets for immunotherapy in childhood cancers. However, the potential for such therapies in targeting these epitopes remains uncertain due to a lack of knowledge of the neoepitope landscape in childhood cancer. Studies to date have focused primarily on missense mutations without exploring gene fusions, which are a major class of oncogenic drivers in pediatric cancer.MethodsWe developed an analytical workflow for identification of putative neoepitopes based on somatic missense mutations and gene fusions using whole-genome sequencing data. Transcriptome sequencing data were incorporated to interrogate the expression status of the neoepitopes.ResultsWe present the neoepitope landscape of somatic alterations including missense mutations and oncogenic gene fusions identified in 540 childhood cancer genomes and transcriptomes representing 23 cancer subtypes. We found that 88% of leukemias, 78% of central nervous system tumors, and 90% of solid tumors had at least one predicted neoepitope. Mutation hotspots in KRAS and histone H3 genes encode potential epitopes in multiple patients. Additionally, the ETV6-RUNX1 fusion was found to encode putative neoepitopes in a high proportion (69.6%) of the pediatric leukemia harboring this fusion.ConclusionsOur study presents a comprehensive repertoire of potential neoepitopes in childhood cancers, and will facilitate the development of immunotherapeutic approaches designed to exploit them. The source code of the workflow is available at GitHub (https://github.com/zhanglabstjude/neoepitope).Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0468-3) contains supplementary material, which is available to authorized users.

Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting

“…Moreover, driver mutations leading to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and other pro-tumorigenic signaling cascades have been revealed to facilitate the establishment of immunosuppressive TME by recruiting MDSCs and T reg cells and reducing major histocompatibility complex (MHC) class I expression and up-regulating expression of PD-L1 and bioenergetic activity in tumor cells [65]. Genomic instability in cancer cells also results in the generation of neopeptides, which are produced from the mutated peptide sequence, including non-synonymous mutations, frame-shifting, intron retaining and fusion genes [66][67][68][69]. Genomic instability in cancer cells also results in the generation of neopeptides, which are produced from the mutated peptide sequence, including non-synonymous mutations, frame-shifting, intron retaining and fusion genes [66][67][68][69].…”

“…Furthermore, genome instability results in the high frequency of genomic mutations and contributes to aberrant functions of oncogenes and tumor suppressors, which support tumor progression and determine cancer immunogenicity. Genomic instability in cancer cells also results in the generation of neopeptides, which are produced from the mutated peptide sequence, including non-synonymous mutations, frame-shifting, intron retaining and fusion genes [66][67][68][69]. Some of these tumor-specific neopeptides can be processed and presented by antigen-presenting cells as neoantigens, which will be further recognized by T cells.…”

Targeted transcriptional profiling of the tumor microenvironment reveals lymphocyte exclusion and vascular dysfunction in metastatic osteosarcoma

“…[10][11][12][13] Bioinformatic analysis of DNA and RNA sequencing data shows that OS tumors express neoantigens, albeit at a low level. 14,15 Why OS patients with advanced and metastatic disease have not benefited from immune checkpoint blockade is an important, yet unresolved, question. [16][17][18] Increasing our comprehension of the OS microenvironment could provide valuable insight into this clinical dilemma and potentially elucidate novel scientific and therapeutic advances towards improved management of this disease.…”

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors

“…In addition, bone sarcomas generally exhibit a low tumor mutational burden (TMB), a predictive biomarker of anti-PD-1/PD-L1 immunotherapy responses [58,59]. Although genetic aberrations are frequent in HGOS, its TMB can be defined as low to moderate, with an average of only seven (or little more) neoepitopes per tumor [60,61], a number that, very likely, is not sufficient to efficiently stimulate the immune system and to determine a good response to anti-PD-1/PD-L1 treatments. Successful immunotherapy based on PD-1/PD-L1 blockades has so far been associated with a high TMB, which facilitates the expression of neoantigens initiating antigen-specific immune responses following immune checkpoint blockade treatment [52,58,62], and with the expression of immune checkpoint molecules.…”