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- Title
Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8<sup>+</sup> T cell responses.
- Authors
Zamora, Anthony E.; Crawford, Jeremy Chase; Allen, E. Kaitlynn; Guo, Xi-zhi J.; Bakke, Jesse; Carter, Robert A.; Abdelsamed, Hossa; Moustaki, Ardiana; Li, Yongjin; Chang, Ti-Cheng; Awad, Walid; Dallas, Mari H.; Mullighan, Charles G.; Downing, James R.; Geiger, Terrence L.; Chen, Taosheng; Green, Douglas R.; Youngblood, Benjamin A.; Zhang, Jinghui; Thomas, Paul G.
- Abstract
Challenging immunogenicity assumptions: Cancers with lower mutation rates, such as pediatric acute lymphoblastic leukemia (ALL), have not shown high immunotherapy response rates, possibly because there are fewer neoepitopes for T cells to recognize. To better understand antitumor responses, Zamora et al. examined samples from pediatric patients with ALL. They predicted peptide neoepitopes that could bind patients' HLA for presentation to T cells and generated tetramers. Somewhat surprisingly, almost all of the predicted peptides were recognizable by patient T cells and induced functional responses in vitro. They detected immunodominance hierarchies and some shared recognition derived from a common ETV6-RUNX1 fusion in tumors. This study shows that low mutation burden tumors such as pediatric ALL should not be assumed to be immunogenically silent and could respond to checkpoint blockade or other T cell–targeted therapies. 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.
- Subjects
T cells; LYMPHOBLASTIC leukemia; CYTOTOXIC T cells; ACUTE leukemia; MAJOR histocompatibility complex; CHILDHOOD cancer
- Publication
Science Translational Medicine, 2019, Vol 11, Issue 498, pN.PAG
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aat8549