Faculty Collaboration Database

Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8⁺ T cell responses. Sci Transl Med 2019 Jun 26;11(498)

Date

06/28/2019

Pubmed ID

31243155

Pubmed Central ID

PMC7020562

DOI

10.1126/scitranslmed.aat8549

Scopus ID

2-s2.0-85068363631 (requires institutional sign-in at Scopus site)   63 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.

Author List

Zamora AE, Crawford JC, Allen EK, Guo XJ, Bakke J, Carter RA, Abdelsamed HA, Moustaki A, Li Y, Chang TC, Awad W, Dallas MH, Mullighan CG, Downing JR, Geiger TL, Chen T, Green DR, Youngblood BA, Zhang J, Thomas PG

Author

Anthony E. Zamora PhD Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antigen Presentation
Antigens, Neoplasm
CD8-Positive T-Lymphocytes
Child
Genetic Heterogeneity
Humans
Immunodominant Epitopes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Reproducibility of Results
Transcription, Genetic