Joshi Raghav, Zhou Ming, Lin Jeffrey H, Song Fei, Fein Daniel, Morrissey Colm, Hu Kun, Poltorak Alexander, Mathew Paul
Tufts Medical Center, Boston, MA, United States.
Dana-Farber Cancer Institute, Boston, MA, United States.
Mol Cancer Res. 2025 Jun 23. doi: 10.1158/1541-7786.MCR-25-0104.
Integrin α5β1 and αv crosstalk in chemotaxis and clonogenic survival of prostate cancer cells is abrogated by a bispecific α5β1/αv antibody (BsAbα5β1/αv), which uniquely induces internalization and lysosomal degradation of target integrins. We hypothesized that the BsAbα5β1/αv inactivates pathological mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAbα5β1/αv uniquely reverses YAP, beta-catenin and FAK nuclear localization compared to monospecific integrin α5β1 and αv antibody controls in basal-type androgen-receptor negative prostate cancer cells. Dual integrin αv and α5 knockdown alone phenocopied the BsAbα5β1/αv effect. Following BsAbα5β1/αv treatment, ATAC-seq studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA-seq indicated down-regulation of Myc/E2F, TGF-beta and epithelial mesenchymal transition (EMT) and upregulation of Type I and II interferon transcriptomic pathways. The BsAbα5β1/αv induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and natural-killer cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. αv 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 DKFZ early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancer and define a novel therapeutic strategy that controls critical immunosuppressive pathways. Implications: Dual integrin α5β1/αv targeting with a bispecific antibody represents a novel therapeutic strategy that reprograms the epigenetic and transcriptomic signature of basal-type prostate cancer with induction of immunological tumor control.
双特异性α5β1/αv抗体（BsAbα5β1/αv）可消除整合素α5β1和αv在前列腺癌细胞趋化性和克隆形成存活中的相互作用，该抗体可独特地诱导靶整合素的内化和溶酶体降解。我们假设BsAbα5β1/αv可使与患者样本中整合素表达相关的病理机械信号通路失活。机制研究表明，与基础型雄激素受体阴性前列腺癌细胞中的单特异性整合素α5β1和αv抗体对照相比，BsAbα5β1/αv可独特地逆转YAP、β-连环蛋白和FAK的核定位。单独敲低整合素αv和α5可模拟BsAbα5β1/αv的作用。在BsAbα5β1/αv处理后，ATAC-seq研究表明TEAD和AP-1家族成员的染色质可及性显著降低。体外和体内RNA-seq表明Myc/E2F、TGF-β和上皮-间质转化（EMT）下调，I型和II型干扰素转录组途径上调。BsAbα5β1/αv诱导CXCL10和CCL5细胞因子分泌、肿瘤免疫浸润以及裸鼠中自然杀伤细胞介导的基础型前列腺癌异种移植物的清除。在快速尸检组织微阵列中，αv整合素高度表达且主要与Myc信号通路相关，这与SU2C转移性去势抵抗性前列腺癌和DKFZ早发性前列腺癌队列的相关数据一致。这些研究将整合素信号与基础型和去势抵抗性前列腺癌的核心生物学联系起来，并定义了一种控制关键免疫抑制途径的新治疗策略。意义：用双特异性抗体靶向整合素α5β1/αv代表了一种新的治疗策略，可通过诱导免疫肿瘤控制来重新编程基础型前列腺癌的表观遗传和转录组特征。
