Selected Articles from This Issue

Bispecific antibodies functioning as T-cell engagers have emerged as a unique treatment strategy to facilitate the interaction between immune cells and cancer cells, forcing clearance of cancerous cells. In prostate cancer, a novel mechanism of immunogenic reprogramming is highlighted with a bispecific integrin α5β1/αv antibody (BsAbα5β1/αv) which triggers the degradation of key integrins implicated in metastatic progression and tumor-stromal interactions. To determine the significance of this loss of integrin expression, Joshi and colleagues investigated the pathological signaling pathways impacted by BsAbα5β1/αv treatment. Subcellular fractionation and RNA sequencing of basal-type prostate cancer cells treated with BsAbα5β1/αv showed reduced nuclear localization and decreased enrichment of gene sets associated with YAP, β-catenin, and FAK compared to controls. Prostate cancer xenografts in nude mice further demonstrated that the BsAbα5β1/αv eliminated clonogenic survival of basal-type tumors and had a significantly greater effect on complete tumor regression and survival than monoclonal antibodies. Engrafted tumors were inflamed with innate immune cells following BsAbα5β1/αv treatment, and tumor elimination required natural killer (NK) cells. Additional studies using RNA sequencing indicated that treatment with BsAbα5β1/αv decreased Myc/E2F, EMT and TGF-β signaling and activated type I and type II interferon responses in vitro and in vivo. Enhanced tumor-autonomous CXCL10 and CCL5 chemokine secretion was demonstrated, which is linked to NK cell recruitment. In vivo clonogenic survival assays performed with isogenic PTEN mutant prostate cancer cells indicated that BsAbα5β1/αv is effective independent of PTEN inactivation. High-frequency target integrin expression in metastatic disease samples was demonstrated, with principal correlation of integrin αv with the Myc pathway and integrin α5 with EMT respectively. Taken together, this study implicates mechanosignaling by integrins αv and α5 in lethal prostate cancer and establishes BsAbα5β1/αv integrin therapy as a novel immunological strategy to control Myc, EMT and TGF-β signaling, critical regulators of the immune-suppressed tumor microenvironment.Luminal progenitor cells have been widely associated with triple-negative breast cancer (TNBC) initiation and progression. In their study, Xu and colleagues found that the long non-coding RNA LINC01235 acts as a transcriptional regulator and modulates the luminal progenitor-like cells of TNBC. Patient-derived organoids of TNBC were analyzed using single cell RNA sequencing and single-molecule RNA fluorescence in situ hybridization, which demonstrated enriched expression of chromatin-associated LINC01235 in the luminal progenitor-enriched cell populations expressing EpCAM and CD49f surface proteins. TNBC cell lines and organoid lines treated with LINC01235-specific antisense oligonucleotides were found to have reduced viability and organoid formation, respectively, compared to the control. MTT and rescue assays performed with a CRISPR/Cas9-mediated LINC01235 knockout TNBC cell line further confirmed LINC01235 mediates proliferation. TNBC cells subjected to chromatin isolation by RNA purification revealed that LINC01235 directly binds to the promoter of NFIB. Correspondingly, the expression of NFIB-regulated NOTCH1 and NOTCH3, were found to be significantly decreased in LINC01235 knockout cells. These findings altogether indicate that LINC01235 functions as a transcriptional regulator of the NFIB/Notch axis and proposes a luminal progenitor cell-associated pathway that may be targeted to improve TNBC outcomes.PAD2, a peptidyl-arginine deiminase, is understood to function as an epigenetic regulator of histone citrullination, but its significance and mechanism in pancreatic ductal adenocarcinoma (PDAC) are largely unknown. To address this gap, Umemura and colleagues utilized in vitro and in vivo models to understand the role of PAD2 in histone citrullination and the tumor microenvironment modulation. Immunohistochemical analysis of PDAC tissues indicated an association between nuclear expression of PAD2 and citrullinated H3R2/8/17 (Cit-H3), both of which were correlated with poor patient prognosis. Expression analyses of knockdown cell line models and PDAC tissues also found that nuclear expression of PAD2 may be RAN-dependent. RNA sequencing, ChIP, and chromatin accessibility assays of PAD2 knockdown cell lines demonstrated that PAD2 catalyzes histone citrullination at the PRUNE1 and E2F1 promoters, thereby enhancing chromatin accessibility and upregulating the expression of these genes. The authors also showed that PAD2-mediated PRUNE1 expression promotes tumor growth and M2 polarization using subcutaneous xenograft models, immunofluorescence staining, and M2 macrophage polarization assays. Syngeneic mouse models and human PDAC tissues supported a tumorigenic PAD2/PRUNE1 axis that influences macrophage subpopulations. Overall, these findings revealed a pathway of PAD2 histone citrullination that impacts the tumor immune microenvironment and patient outcomes.