新型双特异性整合素 α5β1/αv 抗体重编程前列腺癌 Myc 调控的基底表型并介导 NK 细胞肿瘤清除

UNLABELLED: Integrin 5 1 and v cross-talk in chemotaxis, and clonogenic survival of prostate cancer cells is abrogated by a bispecific 5 1/ v antibody (BsAb 5 1/ v), which uniquely induces internalization and lysosomal degradation of target integrins.

We hypothesized that the BsAb 5 1/ v inactivates pathologic mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAb 5 1/ v uniquely reverses Yes-associated protein, -catenin, and focal adhesion kinase nuclear localization compared with monospecific integrin 5 1 and v antibody controls in basal-type androgen receptor-negative prostate cancer cells. Dual integrin v and 5 knockdown alone phenocopied the BsAb 5 1/ v effect. Following BsAb 5 1/ v treatment, Assay for Transposase-Accessible Chromatin using sequencing studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA sequencing indicated downregulation of Myc/E2F, TGF- , and epithelial-mesenchymal transition and upregulation of type I and II IFN transcriptomic pathways.

The BsAb 5 1/ v induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and NK cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. v integrin was highly expressed and principally correlated with the Myc signaling pathway in rapid autopsy tissue microarrays, consistent with correlative data from the SU2C metastatic castration-resistant prostate cancer and Deutsches Krebsforschungszentrum early-onset prostate cancer cohorts.

These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancers and define a novel therapeutic strategy that controls critical immunosuppressive pathways. IMPLICATIONS: Dual integrin 5 1/ v targeting with a bispecific antibody represents a novel therapeutic strategy that reprograms the epigenetic and transcriptomic signatures of basal-type prostate cancer with induction of immunologic tumor control.