Pediatric acute lymphoblastic leukemia (ALL) may be more vulnerable to immunotherapies than previously thought, according to researchers.
Anthony Zamora
High-mutation-burden tumors have the same overall T-cell response magnitude as low-mutation-burden tumors, but it is distributed among a larger mutation landscape, leading to many mutations eliciting small or undetectable responses.
Prior studies suggested that tumors with a low mutational burden don’t elicit strong antitumor responses and therefore aren’t very susceptible to immunotherapy.
Now, researchers have found evidence to suggest that pediatric ALL induces “robust antitumor immune responses” despite a low mutational burden. The investigators identified tumor-associated CD8+ T cells that responded to 86% of neoantigens tested and recognized 68% of neoepitopes tested.
Anthony E. Zamora, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues recounted these findings in Science Translational Medicine.
The researchers analyzed samples from pediatric patients with ETV-associated ALL (n = 9) or ERG-associated ALL (n = 2) to determine how endogenous CD8+ T cells respond to patient-specific cancer neoantigens.
The investigators first assessed the ability of tumor-specific mutations and gene fusions to generate neoepitopes, or neoantigens predicted to bind patient-specific human leukocyte antigen (HLA) proteins. The team identified 5-28 neoepitopes per patient, including epitopes that spanned the fusion junction in patients with ETV6-RUNX1 fusions.
The researchers then tested whether CD8+ tumor infiltrating lymphocytes (TILs) were directly responsive to mutated neoepitopes. They observed cytokine responses across patient samples, noting that 31 of the 36 putative neoantigens tested (86%) were “immunogenic and capable of inducing robust cytokine responses.”
Next, the investigators mapped TIL responses to specific epitopes using patient-specific tetramers that corresponded to the previously identified neoepitopes. Seventeen of the 25 patient-specific tetramers (68%) bound to TILs above the background set by irrelevant HLA-matched tetramers.
“Within those responses, we observed immunodominance hierarchies among the distinct TIL populations, with a majority of tetramer-bound CD8+ T cells restricted to one or two putative neoepitopes,” the researchers noted.
The team also pointed out that seven of nine patients tested had CD8+ T cells that responded to ETV6-RUNX1.
Finally, the investigators performed transcriptional profiling of ALL-specific CD8+ TILs to assess inter- and intrapatient heterogeneity. The team identified three hierarchical clusters, which were characterized by transcriptional factors and regulators associated with:
- Functional effector CD8+ T cells (TBX21 and EOMES).
- Dysfunctional CD8+ T cells (STAT1/3/4, NR4A2/3, and BCL6).
- Exhausted CD8+ T cells (EOMES, MAF, PRDM1, and BATF).
Considering these findings together, the researchers concluded that “pediatric ALL elicits a potent neoepitope-specific CD8+ T-cell response.” Therefore, adoptive T-cell, monoclonal antibody, and targeted T-cell receptor therapies “should be explored” in pediatric ALL.
This research was supported by the National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, Key for a Cure Foundation, and American Lebanese Syrian Associated Charities. The researchers disclosed patent applications and relationships with Pfizer, Amgen, and other companies.
SOURCE: Zamora AE et al. Sci. Transl. Med. 2019 Jun 26. doi: 10.1126/scitranslmed.aat8549.