TY - JOUR
T1 - VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells
AU - Pinho, Sandra
AU - Wei, Qiaozhi
AU - Maryanovich, Maria
AU - Zhang, Dachuan
AU - Balandrán, Juan Carlos
AU - Pierce, Halley
AU - Nakahara, Fumio
AU - Di Staulo, Anna
AU - Bartholdy, Boris A.
AU - Xu, Jianing
AU - Borger, Daniel K.
AU - Verma, Amit
AU - Frenette, Paul S.
N1 - Funding Information:
S.P., Q.W. and P.S.F. are co-inventors on a patent application using anti-VCAM1 antibodies (patent W02017205560A1). P.S.F. serves as a consultant for Pfizer, has received research funding from Ironwood Pharmaceuticals and is a shareholder of Cygnal Therapeutics. The remaining authors declare no competing interests.
Funding Information:
We thank J. W. Pollard for providing Csf1r-iCre mice, T. Papayannopoulou for providing Vcam1 mice, T. Takai and M. Rothenberg for providing Pirb mice and S. A. Armstrong for providing the MLL-AF9 construct. We thank C. Prophete, C. Cruz, P. Ciero, G. Amatuni and A. Landeros for technical assistance, the University of Illinois and the Einstein Flow Cytometry Core Facility for cell sorting assistance, U. Steidl, A. Zahalka and K. Chronis for scientific discussions, and S. V. Buhl and M. D. Scharff of the Macromolecule Therapeutics Core at Einstein for technical assistance and guidance with VCAM1 mAb generation. S.P. and M.M. were supported by a New York Stem Cell Foundation-Druckenmiller Fellowship, J.C.B. by a Pew Latin America Fellowship and CONACYT (México), H.P. by a Training Program in Cellular and Molecular Biology and Genetics (T32 GM007491), D.K.B. by a NIH training grant (T32GM007288) and F.N. by the Japanese Society for the Promotion of Science. We thank the NIH (DK056638, HL069438, HL116340), the Leukemia and Lymphoma Society (LLS-TRP 6475-15) and the New York State Department of Health (NYSTEM IIRP C029570 and C029154) for support of the P.S.F. laboratory and the Cancer Center, University of Illinois Cancer Biology Targeted Grant for support of S.P. During the resubmission of this manuscript Dr Paul S. Frenette passed away on 26 July 2021. floxed −/−
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85125137667&partnerID=8YFLogxK
U2 - 10.1038/s41556-022-00849-4
DO - 10.1038/s41556-022-00849-4
M3 - Article
C2 - 35210567
AN - SCOPUS:85125137667
SN - 1465-7392
VL - 24
SP - 290
EP - 298
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 3
ER -
