Targeting melanoma cell-intrinsic beta2 integrin inhibits ICAM-1-mediated tumor progression

Integrin b2 is an essential mediator of immune cell activation and trafficking via interaction with intercellular adhesion molecule (ICAM)-1. Expression of b2 integrins is thought to be restricted to cells of the hematopoietic lineage. Here we demonstrate nonhematopoietic expression and CD44-dependent induction and activation of integrin b2 by malignant melanoma cells. Tumor cell-b2 in patient primary melanomas correlates with sentinel lymph node metastases, mediates adhesion to ICAM-1, and promotes tumor progression in preclinical models of human and murine melanoma. Consistently, inhibition of melanoma cell-intrinsic b2 integrin using blocking antibodies or CRISPR/Cas9-based b2 gene knockout potently suppresses ICAM-1-dependent melanoma cell adhesion, tumor growth, and metastatic dissemination. Melanoma cell-b2:ICAM-1 interaction stimulates downstream Wnt pathway components, including non-canonical Wnt5a, the pharmacologic inhibition of which reverses protumorigenic melanoma-b2 integrin activity. This work identifies a tumor cell-intrinsic integrin b2:ICAM-1 protumorigenic axis as a bona fide cancer therapeutic target in melanoma. Overall design: CRISPR/Cas9-based integrin b2 gene knockout (KO) and respective control YUMM5.2 melanoma cell variants were generated and inoculated subcutaneously into immunodeficient nonobese diabetic/severe combined immunodeficiency (NOD/SCID) IL-2Rg(-/-) KO (NSG), C57BL/6, or ICAM-1tm1Jcgr KO C57BL/6 mice. Total mRNA was sequenced from freshly harvested control and b2 integrin KO tumor biospecimens from each strain (n=2-4 per group).