VIP/VPAC信号作为TP53突变型急性髓系白血病中的吞噬检查点

Background: Acute myeloid leukemia (AML) remains one of the most lethal hematologic malignancies, especially in TP53-mutated disease where standard chemotherapy provides poor long-term survival. Immune evasion by myeloid cells in the tumor microenvironment is a major barrier to cure. We hypothesized that targeting vasoactive intestinal peptide (VIP)/VIP receptor (VPAC) signaling would overcome myeloid cell-mediated immunosuppression and enhance anti-tumor responses in AML. Methods: RNA-seq differential expression, survival analyses, and flow cytometry of AML bone marrow and PBMC were used to profile VIP/VPAC expression and myeloid versus blast compartments in TP53-mutated and non-mutated cases. TP53-wildtype and TP53 loss-of-function human and murine AML cell lines were used to measure VIP production by ELISA and macrophage phagocytosis of VIP-producing versus low-VIP cells in M1- and M2-like co-culture assays. In vivo efficacy of the long-acting VIP receptor antagonist ANT308 and its IgG4 Fc fusion ANT308-Fc3 was evaluated in C1498 and WEHI3 AML models, including VIP, VPAC1, and VPAC2 knockout hosts. Results: VIP expression was elevated in PBMC from ~36% of AML patients compared with healthy donors and was enriched in TP53-mutated cases. High VIP expression and TP53 loss-of-function each associated with inferior survival in cBioPortal datasets. RNA-seq showed that TP53-mutated AML is characterized by increased VIP and immunoregulatory pathway signatures together with reduced apoptosis and effector CD8⁺ T-cell-associated genes. Secretome analysis of human leukemia cells demonstrated higher VIP secretion from TP53 loss-of-function lines than from TP53-wildtype THP-1, confirming leukemia-intrinsic VIP production. In patient samples, both CD34⁺ blasts and CD34⁻ myeloid cells contained VIP⁺ cells, but non-blast myeloid cells accounted for most VIP⁺ events, indicating they are a major VIP source in the AML microenvironment. ANT308 enhanced phagocytosis of VIP-secreting WEHI3 leukemia cells by both M1- and M2-like macrophages but did not alter phagocytosis of VIP-low C1498 cells, supporting VIP as a phagocytosis checkpoint in AML. Consistent with a host contribution, VIP-, VPAC1-, or VPAC2-knockout mice bearing C1498 leukemia showed improved survival relative to wild-type mice. In vivo treatment of wild-type C1498-bearing mice with ANT308 or the long-acting Fc fusion ANT308-Fc3 eradicated established leukemia in up to 65% of animals. Conclusions: VIP/VPAC signaling defines a previously unrecognized phagocytosis checkpoint that reinforces myeloid immunosuppression in AML and is linked to TP53-mutated disease. VPAC antagonism with ANT308-Fc3 restores macrophage phagocytosis and produces durable leukemia control in preclinical models, supporting clinical development of VPAC-targeted immunotherapy for high-risk AML.