Research Perspectives:

Targeting cancer stem cells via integrin β4

Hannah E. Dobson, Shasha Ruan, Alfred E. Chang, Max S. Wicha and Qiao Li _

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Oncotarget. 2021; 12:1850-1858. https://doi.org/10.18632/oncotarget.27977

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Hannah E. Dobson1, Shasha Ruan1,2, Alfred E. Chang1, Max S. Wicha1 and Qiao Li1

1 Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA

2 Department of Clinical Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China

Correspondence to:

Qiao Li, email: [email protected]

Keywords: cancer stem cells; ITGβ4; dendritic cell vaccine; bispecific antibody; T cells

Received: April 15, 2021     Accepted: May 13, 2021     Published: August 31, 2021

Copyright: © 2021 Dobson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Integrins mediate cell-cell interactions and communication with the extracellular matrix (ECM). These transmembrane protein receptors allow binding between a cell and its surroundings, initiating a breadth of intracellular signaling resulting in proliferation, differentiation, survival, or migration. Such responses have made integrins an attractive target for cancer therapy. Self-renewing and highly tumorigenic cancer stem cells (CSCs) are most resistant to traditional radiation treatment and chemotherapy, and therefore may contribute directly to the metastasis and relapse of the disease. In both the 4T1 mouse metastatic mammary tumor model and SCC7 head and neck squamous cell carcinoma model, integrin β4 (ITGB4) was expressed on ALDHhigh 4T1 and SCC7 CSCs. Using two immunological approaches, we targeted ITGB4 through 1) ITGB4 protein-pulsed dendritic cell (ITGB4-DC) vaccination or 2) via anti-CD3/anit-ITGB4 bispecific antibody (ITGB4 BiAb)-armed T cell adoptive transfer. These two therapies reduced ITGB4-expressing CSCs and inhibited local tumor growth and lung metastasis through ITGB4 specific cellular and humoral immune responses. Additionally, the combination of anti-PD-L1 immunotherapy with our two ITGB4-targeted approaches significantly improved treatment efficacy. We also found increased concentrations of serum IFN-γ and IL-6 in the 4T1 and SCC7 models which may help define future directions of this ITGB4-targeted study. Together, these results emphasize ITGB4 as a practical CSC immunological target with possible therapeutic benefits across tumor types with high ITGB4 expression.

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