Abstract A51: Early-life infection delays B cell precursor leukemia onset in Eu-Ret mice via an IL-23-dependent depletion of leukemia-initiating cells
Bibliographic record
Abstract
Abstract An influence of infection on the development of pediatric acute lymphoblastic leukemia (ALL) is supported by epidemiological studies that have uncovered associations between infection history and ALL risk. However, these studies have produced discordant results, with both reduced and increased risk having been reported, and a mechanistic explanation remains elusive. Back-tracking studies have demonstrated that the development of ALL depends upon the long-term survival and evolution of an abnormal leukemia-initiating cell (LIC) population that arises in utero. However, the occurrence of detectable LICs at birth is significantly greater than the incidence of leukemia, suggesting that events during the pre-leukemic phase may influence disease progression by altering the fate of these cells. In this study, we use the B cell precursor (BCP) leukemia-prone Emu-RET transgenic mouse to investigate whether infection exposure is capable of altering disease progression via changes in LIC survival. Epidemiological studies have associated low grade, sub-clinical infections with reduced ALL risk, while more severe infections are associated with increased risk. To mimic a sub-clinical infection, we exposed Emu-RET mice to an ActA-/- attenuated strain of Listeria monocytogenes (Lm) prior to leukemia onset. Infection resulted in a significant depletion of LICs in spleen and bone marrow (p<0.0001) and delayed disease onset by approximately fifty days (p<0.0001). The timing of infection has been identified as a critical variable in epidemiological studies assessing ALL risk. To evaluate whether timing was a factor in our model, we administered Lm to either neonatal (Day 6) or adult (Day 34) Emu-RET mice and measured LIC numbers. Only infections at the early time point were capable of depleting the LIC population (D6 depletion: p<0.0001; D34 depletion: p=0.4371 ). This time dependence was maintained when infection dose was normalized based on the weight of recipient mice. Importantly, given that no single infectious agent has been identified in the ALL epidemiological studies, we observed a similar age-dependent response pattern following nasal infection with live non-attenuated Murine gamma-herpesvirus (MHV)-68. An inherent deficit in IL-12p35 production in neonates leads to a skewing of the early-life immune system towards IL-23-driven Th17 responses in both mice and humans. Considering this age-related immune difference and reports of IL-23 as an anti-leukemic factor, we hypothesized that IL-23 and its downstream effectors mediate the infection-dependent LIC depletion. Using targeted blocking-antibodies, we found that both Lm and MHV-68 infection-associated depletion of LICs was entirely dependent on IL-12p40 (p<0.0001). IL-12p75 is not required for this depletion (p=0.889), confirming the role of IL-23 as a critical factor required for the early-life depletion of LICs. Overall, this study provides the first mechanistic explanation for the epidemiological link between early-life infections and reduced risk of pediatric ALL by demonstrating that low-grade infections administered during a brief neonatal period cause depletion of the in utero-derived LIC population. Citation Format: Mario Fidanza, Sheka Y. Aloyouni, Sehyun Cho, Alix E. Seif, Soren Gantt, Tobias R. Kollmann, Gregor SD Reid. Early-life infection delays B cell precursor leukemia onset in Eu-Ret mice via an IL-23-dependent depletion of leukemia-initiating cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A51.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".