VCAM1 Mediates Innate Immune Tolerance of Hematopoietic and Leukemic Stem Cells

Hematopoietic stem cells (HSC) replenish the hematopoietic system after transplant, with vascular cell adhesion molecule-1 (VCAM1) mediating the movement of HSCs between the blood and bone marrow (BM). Pinho and colleagues further investigated the role of VCAM1 in this process and demonstrated high expression of VCAM1 on BM HSCs. Transplantation of haplotype-mismatched Vcam1^Csf1r-iCre BM cells, which are VCAM1-depleted HSCs, into lethally irradiated mice reduced recipient mouse survival and did not show any contribution to repopulation, suggesting the regulation of engraftment by VCAM1 on HSCs. Time-course studies revealed a reduction in VCAM1-depleted progenitor cell contributions to the blood 4 days after transplantation, which became undetectable after 2 weeks. This transplant failure was determined to be mediated by phagocytic clearance, and further investigation showed that deletion of VCAM1 in a setting of haplotype-mismatched transplantation demonstrated severe engraftment defects and death of approximately 76% of the recipients. Gr1^lo monocytes were the most active in clearing these cells with CD8⁺ T-cell deletion not rescuing this effect. However, the engraftment defects of haplotype-mismatched VCAM1-deficient cells were rescued upon defective MHC class I expression, suggesting that the combined effect of VCAM1 deletion and the recognition of mismatched MHC class I molecules on HSCs leads to phagocyte activation. Furthermore, the inhibitory receptor expressed by myeloid phagocytes, PIR-B, was shown to be required for the transmission of VCAM1’s immune-suppressive signals. Analysis into the role of VCAM1 in acute myeloid leukemia (AML) revealed a sevenfold increase in its expression on AML cells as well as that a reduction in its expression concomitantly reduced leukemia stem cell infiltration. Preclinical studies in syngeneic mouse models of AML injected with an anti-VCAM1 antibody showed an extension to survival with no reduction in healthy HSC numbers. Additionally, in human AML, VCAM1 overexpression was found to increase AML cell tumorigenicity. Overall, this study reveals a “don't eat me” function of VCAM1 on HSCs and suggests use of anti-VCAM1 therapy could provide a potential combination treatment along with chemotherapy to increase innate immune response against AML.

Pinho S, Wei Q, Maryanovich M, Zhang D, Balandrán JC, Pierce H, et al. VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells. Nat Cell Biol 2022 Feb 24 [Epub ahead of print].

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