BackgroundDespite the success of immune checkpoint blockade therapy in the treatment of certain cancer types, only a small percentage of patients with solid malignancies achieve a durable response. Consequently, there is a need to develop novel approaches that could overcome mechanisms of tumor resistance to checkpoint inhibition. Emerging evidence has implicated the phenomenon of cancer plasticity or acquisition of mesenchymal features by epithelial tumor cells, as an immune resistance mechanism.MethodsTwo soluble factors that mediate tumor cell plasticity in the context of epithelial-mesenchymal transition are interleukin 8 (IL-8) and transforming growth factor beta (TGF-β). In an attempt to overcome escape mechanisms mediated by these cytokines, here we investigated the use of a small molecule inhibitor of the IL-8 receptors CXCR1/2, and a bifunctional agent that simultaneously blocks programmed death ligand 1 (PD-L1) and traps soluble TGF-β.ResultsWe demonstrate that simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells, significantly enhancing T-cell infiltration and activation in tumors, and leading to improved antitumor activity.ConclusionsThis study highlights the potential benefit of combined blockade of CXCR1/2 and TGF-β signaling for modulation of tumor plasticity and potential enhancement of tumor responses to PD-L1 blockade. The data provide rationale for the evaluation of this novel approach in the clinic.

Purpose Whether it is safe for estrogen receptor positive (ER+) breast cancer patients to consume soy isoflavone genistein (GEN) remains controversial. We compared the effects of GEN intake mimicking either Asian (lifetime) or Caucasian (adulthood) intake patterns to that of starting its intake during tamoxifen (TAM) therapy using a preclinical model. Experimental Design Female Sprague-Dawley rats were fed an AIN93G diet supplemented with 0 (control diet) or 500 ppm GEN from postnatal day 15 onwards (lifetime GEN). Mammary tumors were induced with 7,12-dimethylbenz(a)anthracene (DMBA), after which a group of control diet fed rats were switched to GEN diet (adult GEN). When the first tumor in a rat reached 1.4 cm in diameter, TAM was added to the diet, and a subset of previously only control diet fed rats also started GEN intake (post-diagnosis GEN). Results Lifetime GEN intake reduced de novo resistance to TAM, compared with post-diagnosis GEN groups. Risk of recurrence was lower both in the lifetime and adult GEN groups than in the post-diagnosis GEN group. We observed downregulation of unfolded protein response (UPR) and autophagy related genes (GRP78, IRE1α, ATF4 and Beclin-1), and genes linked to immunosuppression (TGFβ and Foxp3), and upregulation of cytotoxic T cell marker CD8a in the tumors of the lifetime GEN group, compared with controls, post-diagnosis, and/or adult GEN groups. Conclusions GEN intake mimicking Asian consumption patterns improved response of mammary tumors to TAM therapy, and this effect was linked to reduced activity of UPR and pro-survival autophagy signaling, and increased anti-tumor immunity.

Introduction: Antithrombotic medications are the subject of multiple transcatheter aortic valve replacement (TAVR) randomized control trials. Pragmatically, decisions are complicated by conditions such as atrial fibrillation (AF) that also require lifetime anticoagulation. Our study examines antithrombotic medications in a real-world cohort to identify risk factors for bleeding by 1-year post-TAVR. Methods: This retrospective study includes 844 patients undergoing transfemoral TAVR between 2015 and 2020. Pre- and post-operative medications, comorbidities, and 1-year outcomes were recorded based on review of the medical record. Antithrombotic regiment decisions were made on a case-by-case basis. Bleeding classification followed VARC2 definitions. Patients were stratified into two groups based on history of AF. Multivariable logistic regression was used to determine independent predictors of bleeding. Results: Among the 844 patients, 290 had comorbid AF (34%). Patients with AF were older (80.3 vs 77.8 years; p<0.001), more frequently had cardiovascular comorbidities, and had lower LVEF (52.4% vs 56.8%; p<0.001). Patients with AF were more likely to experience major or life-threatening bleeding (10% vs 5%; p<0.001), but there were no differences in rates of myocardial infarction, cerebrovascular accident, nor death by 1-year follow-up. After controlling for risk factors including anticoagulation and increases to antithrombotic regiment post-operatively, the independent risk predictors of major or life-threatening bleed included female sex [OR 1.522 (1.118-1.741); p=0.018], severe baseline anemia [2.938 (1.146-7.533); p=0.025], and atrial fibrillation [2.195 (1.206-3.997); p=0.010]. Conclusions: Female sex, severe baseline anemia, and comorbid atrial fibrillation are predictors of major or life-threatening bleed by 1 year in patients undergoing transfemoral TAVR, independent of antithrombotic regiment.

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<p>UPR gene expression levels of mammary glands and tumors of animals before TAM treatment.</p>