Ectopic integrin β1 overproduction by squamous carcinoma cells contributes to immune evasion-associated metastasis

Distant metastasis often predicts poor survival for squamous cell carcinoma (SCC) patients. To identify potential targets for metastatic SCCs, we performed spatial profiling of SCC specimens from head and neck cancer patients to identify stage-associated markers. Laminin-binding integrins, normally restricted to basal keratinocytes, were enriched in Stage IV-A intratumoral regions vs Stage II/III SCCs, consistent with poor survival correlations of these integrins in TCGA. Due to the association of multiple laminin-binding integrins with poor prognosis, we assessed their collective impact on metastasis by knocking down integrin β1, a common partner of α-integrins, in mouse SCC cells derived from keratin 15 (K15)⁺ stem cells harboring a Kras^G12D mutation and Smad4 deletion (Smad4^-/-). SCC cell lines derived from primary tumors with or without spontaneous lung metastasis were established. Metastatic SCC cells had higher levels of laminin-binding integrins than non-metastatic SCC cells derived from this model. Knockdown of the integrin β1 gene (shITGB1) in metastatic SCC cells ablated lung metastases following implantation into immunocompetent but not immunocompromised hosts. RNA sequencing of control/shITGB1 murine SCC cells identified that integrin β1 was linked to pathways related to leukocyte recruitment. At the protein level, inflammatory cytokine arrays and immunostaining of metastatic murine tumors revealed that metastatic SCCs exhibited elevated myeloid chemotactic proteins, granulocyte infiltration, and low CD8 T cell presence. shITGB1 reversed these patterns. Conversely, CD8α depletion enabled shITGB1 SCC cells to reestablish lung metastasis in immunocompetent hosts. Our results reveal an unappreciated role of SCC cell-produced integrin β1 in driving immune suppression-associated metastasis.