Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8+ T cell responses

Anthony E. Zamora, Jeremy Chase Crawford, E. Kaitlynn Allen, Xi Zhi J. Guo, Jesse Bakke, Robert A. Carter, Hossam A. Abdelsamed, Ardiana Moustaki, Yongjin Li, Ti Cheng Chang, Walid Awad, Mari H. Dallas, Charles G. Mullighan, James R. Downing, Terrence L. Geiger, Taosheng Chen, Douglas R. Green, Benjamin A. Youngblood, Jinghui Zhang, Paul G. Thomas

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Cancer arises from the accumulation of genetic alterations, which can lead to the production of mutant proteins not expressed by normal cells. These mutant proteins can be processed and presented on the cell surface by major histocompatibility complex molecules as neoepitopes, allowing CD8+ T cells to mount responses against them. For solid tumors, only an average 2% of neoepitopes predicted by algorithms have detectable endogenous antitumor T cell responses. This suggests that low mutation burden tumors, which include many pediatric tumors, are poorly immunogenic. Here, we report that pediatric patients with acute lymphoblastic leukemia (ALL) have tumor-associated neoepitope-specific CD8+ T cells, responding to 86% of tested neoantigens and recognizing 68% of the tested neoepitopes. These responses include a public neoantigen from the ETV6-RUNX1 fusion that is targeted in seven of nine tested patients. We characterized phenotypic and transcriptional profiles of CD8+ tumor-infiltrating lymphocytes (TILs) at the single-cell level and found a heterogeneous population that included highly functional effectors. Moreover, we observed immunodominance hierarchies among the CD8+ TILs restricted to one or two putative neoepitopes. Our results indicate that robust antitumor immune responses are induced in pediatric ALL despite their low mutation burdens and emphasize the importance of immunodominance in shaping cellular immune responses. Furthermore, these data suggest that pediatric cancers may be amenable to immunotherapies aimed at enhancing immune recognition of tumor-specific neoantigens.

Original languageEnglish
Article numbereaat8549
JournalScience Translational Medicine
Volume11
Issue number498
DOIs
StatePublished - 2019

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