VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells

Haematopoietic stem cells (HSCs) home to the bone marrow (BM) via, in part, the interactions with Vascular Cell Adhesion Molecule-1 (VCAM1)(1–3). Once into the BM, HSCs are vetted by perivascular phagocytes to ensure their self-integrity. Here, we show that VCAM1 is also expressed on healthy HSCs and upregulated on leukaemic stem cells (LSCs) where it serves as a quality-control checkpoint for entry into BM by providing ‘don’t-eat-me’ stamping in the context of major histocompatibility complex (MHC) class-I presentation. While haplotype-mismatched HSCs can engraft, Vcam1 deletion, in the setting of haplotype mismatch, leads to impaired haematopoietic recovery due to HSC clearance by mononuclear phagocytes. Mechanistically, VCAM1 ‘don’t-eat-me’ activity is regulated by ß2-microglobulin MHC presentation on HSCs and paired Ig-like receptor-B (PIR-B) on phagocytes. VCAM1 is also used by cancer cells to escape immune detection as its expression is upregulated in multiple cancers, including acute myeloid leukaemia (AML), where high expression associates with poor prognosis. In AML, VCAM1 promotes disease progression while VCAM1 inhibition or deletion reduces leukaemia burden and extends survival. These results suggest that VCAM1 engagement regulates a critical immune-checkpoint gate in the BM, and offers an alternative strategy to eliminate cancer cells via modulation of the innate immune tolerance.