In tumor biopsies from pediatric patients with acute lymphoblastic leukemia (ALL), which typically has a low mutation burden, Zamora et al. identified between 5 and 28 predicted neoantigens per patient, with 86% of tested neoantigens and 68% of tested neoepitopes eliciting a neoepitope-specific CD8+ TIL response ex vivo. Most patients with ETV6-RUNX1 genomic fusion produced a corresponding CD8+ TIL response. In some TILs, responses were dominated by only one or two putative neoepitopes. The composition of ALL-specific CD8+ TILs varied within and between patients, and included functional, dysfunctional, and exhausted states.
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.
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105,
Author Info: (1) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (2) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (3) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (4) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA. (5) Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Department of Foundational Sciences, College of Medicine, Central Michigan University, Mount Pleasant, MI 48858, USA. (6) Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (7) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (8) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (9) Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (10) Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (11) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (12) Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (13) Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (14) Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (15) Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (16) Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (17) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (18) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (19) Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. (20) Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. paul.thomas@stjude.org. Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
