Pediatric Cancers with Low Mutation Burden Can Be Immunogenic

Therapies targeting cancers via T cell–mediated mechanisms have primarily been studied in adult solid tumors, which generally have a high mutational burden compared with pediatric cancers, but it's not clear whether pediatric cancers with relatively low tumor mutation burden have inherently poor T-cell responses. Zamora and colleagues set out to investigate the endogenous CD8⁺ T-cell response in pediatric acute lymphoblastic leukemia (ALL). In a cohort of 11 patients with pediatric ALL, predicted neoepitopes and bone marrow–infiltrating CD8⁺ T cells were observed in all patients, and in a directly ex vivo analysis of cytokine production by CD8+ T cells co-cultured with artificial antigen-presenting cells and neoantigen peptides in the three patients with the greatest number of CD8⁺ T cells, all tested peptides led to at least some response—sometimes a strong response—in each patient sample. Further investigation using direct stimulation of bone marrow from six patients revealed that all samples responded to one or more neoantigenic peptides tested. An analysis of global neoantigen-specific CD8⁺ T-cell response in six patients revealed that each had at least one neoepitope-specific CD8⁺ tumor-infiltrating lymphocyte (TIL) population. Demonstrating that the neoepitopes caused CD8⁺ T cells to mount an antitumor response, 68% of 25 tested patient-specific tetramers bound TILs above the level of nonspecific HLA-matched tetramers. Collectively, these findings show that there is a CD8⁺ T-cell response with a substantial number of neoepitopes being targeted by the immune system in pediatric ALL. Within a patient, these responses formed hierarchies of immunodominance. CD8⁺ T cells could also target common gene fusions observed in ALL, such as the ETV6–RUNX1 fusion seen in 20%–25% of pediatric ALL. Transcriptional profiling of neoepitope-specific CD8⁺ TILs revealed heterogeneity across patients and was consistent with functional effector differentiation. Although studies with larger patient cohorts are needed to confirm the broad applicability of these findings, these results suggest that some pediatric cancers may be candidates for immunotherapies targeting tumor-specific neoantigens.

Zamora AE, Crawford JC, Allen EK, Guo XJ, Bakke J, Carter RA, et al. Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8⁺ T cell responses. Sci Transl Med 2019;11:eaat8549.

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