Acute Myeloid Leukemia Stem Cells Escape Innate Immune Surveillance by Macrophages through Interaction with SIRPα
Bibliographic record
Abstract
Abstract Abstract 499 Introduction: Using a genome-wide positional cloning approach, we previously identified NOD-derived Sirpα as the gene required for support of normal human hematopoiesis in NOD.SCID xenotransplantation assays. NOD.SCID mice bearing other polymorphic Sirpα alleles (e.g. NOD.NOR-Idd13.SCID) do not support human engraftment due to lack of interaction between CD47 expressed on human hematopoietic cells and SIRPα expressed on host macrophages. CD47-SIRPα interaction is also critical for engraftment of human acute myeloid leukemia stem cells (AML-SC): homing, engraftment and migration are all significantly impaired in NOD.NOR-Idd13.SCID compared to NOD.SCID mice. However, AML-SC from different patients are heterogeneous in their ability to engraft NOD.NOR-Idd13.SCID mice, suggesting variable ability to evade innate immune surveillance. We undertook investigations of the mechanisms underlying the decreased engraftment ability of AML-SC in NOD.NOR-Idd13.SCID mice, a better understanding of which will aid in optimizing potential therapeutic approaches aimed at disrupting CD47-SIRPα signaling in AML. Result: To investigate the cellular components of innate immunity that impair AML-SC function, we depleted macrophages in NOD.NOR-Idd13.SCID mice by treatment with clodronate liposomes. Following intravenous injection, homing of AML cells (n=2 patient samples) to bone marrow (BM) and spleen of NOD.NOR-Idd13.SCID mice was not detectable in control mice but was increased in clodronate-treated mice to levels similar to those seen in clodronate-treated NOD.SCID mice. Thus, impaired homing resulting from lack of interaction between CD47 on AML cells and SIRPα on macrophages is rescued by macrophage depletion. To examine the role of macrophages in engraftment and migration of AML-SC, we transplanted NOD.NOR-Idd13.SCID mice intrafemorally with primary AML cells (n=3 patient samples) and treated them weekly with clodronate for 8 weeks. In previous experiments, these AML samples were unable to engraft NOD.NOR-Idd13.SCID mice, or could only engraft the injected femur without migration to other hematopoietic sites. In contrast, clodronate-mediated macrophage depletion in these mice allowed substantial leukemic engraftment by all samples not only in the injected femur, but also in non-injected bones, the spleen and peripheral blood. Thus, evasion of innate immune surveillance by macrophages through interactions between CD47 on AML cells and SIRPα on macrophages is critical for engraftment of AML-SC. To investigate the mechanism of macrophage-mediated impairment of AML-SC function in NOD.NOR-Idd13.SCID mice, we established an in vitro phagocytosis assay using BM-derived macrophages from NOD.SCID and NOD.NOR-Idd13.SCID mice. NOD.NOR-Idd13.SCID macrophages prestimulated with interferon-γ and lipopolysaccharide consistently showed higher levels of phagocytosis of human AML cells in vitro compared to NOD.SCID macrophages. This finding suggests that macrophages eliminate AML cells in vivo through phagocytosis, a process that is inhibited by CD47-SIRPα signaling. The critical importance of CD47-SIRPα signaling for AML-SC function led us to develop a novel human SIRPα (hSIRPα)-Fc fusion protein antagonist for therapy of AML. In pilot studies, in vitro pretreatment of AML cells efficiently blocked homing, engraftment and dissemination following xenotransplantation into NOD.SCID mice. More importantly, in vivo hSIRPα-Fc treatment of NOD.SCID mice repopulated with human AML resulted in dramatic decrease of the leukemic burden in all hematopoietic tissues. Conclusion: Our data show that the interaction between CD47 on AML-SC and SIRPα expressed on host macrophages is critical for the leukemic clone to evade macrophage-mediated innate immune attack. Disruption of this signaling axis, as with hSIRPα-Fc fusion proteins, is an effective therapeutic approach for eradication of AML-SC. Disclosures: Theocharides: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Jin: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Dick: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Danska: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding. Wang: Trillium Therapeutics Inc. (TTI): Patents & Royalties, Research Funding.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".