VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells

Sandra Pinho, Qiaozhi Wei, Maria Maryanovich, Dachuan Zhang, Juan Carlos Balandrán, Halley Pierce, Fumio Nakahara, Anna Di Staulo, Boris A. Bartholdy, Jianing Xu, Daniel K. Borger, Amit Verma, Paul S. Frenette

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Haematopoietic stem cells (HSCs) home to the bone marrow via, in part, interactions with vascular cell adhesion molecule-1 (VCAM1)1–3. Once in the bone marrow, 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 bone marrow by providing ‘don’t-eat-me’ stamping in the context of major histocompatibility complex class-I (MHC-I) presentation. Although 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 β2-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, whereas VCAM1 inhibition or deletion reduces leukaemia burden and extends survival. These results suggest that VCAM1 engagement regulates a critical immune-checkpoint gate in the bone marrow, and offers an alternative strategy to eliminate cancer cells via modulation of the innate immune tolerance.

Original languageEnglish (US)
Pages (from-to)290-298
Number of pages9
JournalNature Cell Biology
Volume24
Issue number3
DOIs
StatePublished - Mar 2022

ASJC Scopus subject areas

  • Cell Biology

Fingerprint

Dive into the research topics of 'VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells'. Together they form a unique fingerprint.

Cite this