Comprehensive immunophenotyping of solid tumor-infiltrating immune cells reveals the expression characteristics of LAG-3 and its ligands.

Background: Immune cell expression profiling from patient samples is critical for the successful development of immuno-oncology agents and is useful to understand mechanism-of-action, to identify exploratory biomarkers predictive of response, and to guide treatment selection and combination therapy strategies. LAG-3 is an inhibitory immune checkpoint that can suppress antitumor T-cell responses and targeting LAG-3, in combination with PD-1, is a rational approach to enhance antitumor immunity that has recently demonstrated clinical success. Here, we sought to identify human immune cell subsets that express LAG-3 and its ligands, to characterize the marker expression profile of these subsets, and to investigate the potential relationship between LAG-3 expressing subsets and clinical outcomes to immuno-oncology therapies. Methods: Comprehensive high-parameter immunophenotyping was performed using mass and flow cytometry of tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs) from two independent cohorts of samples from patients with various solid tumor types. Profiling of circulating immune cells by single cell RNA-seq was conducted on samples from a clinical trial cohort of melanoma patients treated with immunotherapy. Results: LAG-3 was most highly expressed by subsets of tumor-infiltrating CD8 T central memory (TCM) and effector memory (TEM) cells and was frequently co-expressed with PD-1. We determined that these PD-1+ LAG-3+ CD8 memory T cells exhibited a unique marker profile, with greater expression of activation (CD69, HLA-DR), inhibitory (TIM-3, TIGIT, CTLA-4) and stimulatory (4-1BB, ICOS) markers compared to cells that expressed only PD-1 or LAG-3, or that were negative for both checkpoints. In contrast to tumors, LAG-3 expression was more limited in circulating immune cells from healthy donors and solid tumor patients. Additionally, we found abundant expression of the LAG-3 ligands MHC-II and galectin-3 in diverse immune cell types, whereas FGL1 and LSECtin were minimally expressed by immune cells in the tumor microenvironment (TME). Lastly, we found an inverse relationship between baseline and on-treatment levels of circulating LAG3 transcript-expressing CD8 memory T cells and response to combination PD-1 and CTLA-4 blockade in a clinical trial cohort of melanoma patients profiled by scRNAseq. Conclusions: These results provide insights into the nature of LAG-3- and ligand-expressing immune cells within the TME, and suggest a biological basis for informing mechanistic hypotheses, treatment selection strategies, and combination immunotherapy approaches to support continued development of dual PD-1 and LAG-3 blockade.

A rare case of BK virus non-hemorrhagic cystitis following lung transplant.

BK virus cystitis is known to occur following hematopoietic stem cell transplant (HSCT), but few cases exist in the literature following lung transplant. Because of the rarity of this presentation, patients may have missed diagnoses and prescribed ineffective treatments. We present our case of an atypical presentation of BK virus cystitis appearing as bladder carcinoma in situ in a lung transplant patient.

Prostatic urethral lift (PUL) clip causing postoperative pain after holmium laser enucleation of the prostate (HoLEP).

Few series exist in the literature of holmium laser enucleation of the prostate (HoLEP) after prostatic urethral lift (PUL). Even less well known are potential complications seen after a patient undergoes PUL followed by HoLEP. We present our case of a unique clinical finding of a PUL clip and suture found in the urethra of a patient after HoLEP.

Race and Age Impact Osteoporosis Screening Rates in Women Prior to Hip Fracture.

Bone mineral density screening and clinical risk factors are important to stratify individuals for increased risk of fracture. In a population with no history of fractures or baseline bone density measurement, black women were less likely to be screened than white counterparts prior to hip fracture. PURPOSE: To evaluate overall BMD (bone mineral density) screening rates within two years of hip fracture and to identify any disparities for osteoporosis screening or treatment in a female cohort who were eligible for screening under insurance and national recommendations. METHODS: Data were obtained from 1,109 female patients listed in the Research Action for Health Network (REACHnet) database, which consists of multiple health partner systems in Louisiana and Texas. Patients < 65 years old or with a history of hip fracture or osteoporosis diagnosis, screening or treatment more than 2 years before hip fracture were removed. RESULTS: Only 223 (20.1%) females were screened within the two years prior to hip fracture. Additionally, only 23 (10%) of the screened patients received treatment, despite 187 (86.6%) patients being diagnosed with osteoporosis or osteopenia. Screening rates reached a maximum of 27.9% in the 75-80 age group, while the 90 + age group had the lowest screening rates of 12%. We found a quadratic relationship between age and screening rates, indicating that the screening rate increases in age until age 72 and then decreases starkly. After adjusting for potential confounders, we found that black patients had significantly decreased screening rates compared to white patients (adjusted OR = .454, 95% CI = .227-.908, p value = .026) which held in general and for patient ages 65-97. CONCLUSION: Despite national recommendations, overall BMD screening rates among women prior to hip fracture are low. If individuals are not initially screened when eligible, they are less likely to ever be screened prior to fracture. Clinicians should address racial disparities by recommending more screening to otherwise healthy black patients above the age of 65. Lastly, treatment rates need to increase among those diagnosed with osteoporosis since all patients went on to hip fracture.

Telemedical Monitoring Based on Implantable Devices-the Evolution Beyond the CardioMEMS™ Technology.

PURPOSE OF THE REVIEW: We aimed to provide an overview of telemedical monitoring and its impact on outcomes among heart failure (HF) patients. RECENT FINDINGS: Most HF readmissions may be prevented if clinical parameters are strictly controlled via telemedical monitoring. Predictive algorithms for patients with cardiovascular implantable electronic devices (e.g., Triage-HF Plus by Medtronic or HeartLogic by Boston Scientific) were developed to identify patients at significantly increased risk of HF events. However, randomized control trial-based data are heterogeneous regarding the advantages of telemedical monitoring in HF patients. The likelihood of adverse clinical outcomes increases when pulmonary artery pressure (PAP) rises, usually days to weeks before clinical manifestations of HF. A wireless monitoring system (CardioMEMS™) detecting changes in PAP was proposed for HF patients. CardioMEMS™ transmits data to the healthcare provider and allows to institute timely intensification of HF therapies. CardioMEMS™-guided pharmacotherapy reduced a risk of HF-related hospitalization (hazard ratio [HR]: 0.72; 95% confidence interval (CI) 0.60-0-0.85; p < 0.01). Relevant developments and innovations of telemedical care may improve clinical outcomes among HF patients. The use of CardioMEMS™ was found to be safe and cost-effective by reducing the rates of HF hospitalizations.

A Systematic Literature Review of Health Utility Values in Breast Cancer.

BACKGROUND: Health utility values (HUVs) are important inputs to the cost-utility analysis of breast cancer interventions. PURPOSE: Provide a catalog of breast cancer-related published HUVs across different stages of breast cancer and treatment interventions. DATA SOURCES: Systematic searches of MEDLINE, MEDLINE In-Process, EMBASE, Web of Science, CINAHL, PsycINFO, EconLit, and Cochrane databases (2005-2017). STUDY SELECTION: Studies published in English that reported mean or median HUVs using direct or indirect methods of utility elicitation for breast cancer. DATA EXTRACTION: Independent reviewers extracted data on a preestablished and piloted form; disagreements were resolved through discussion. DATA ANALYSIS: Mixed-effects meta-regression using restricted maximum likelihood modeling was conducted for intervention type, stage of breast cancer, and typical clinical and treatment trajectory of breast cancer patients to assess the effect of study characteristics (i.e., sample size, utility elicitation method, and respondent type) on HUVs. DATA SYNTHESIS: Seventy-nine studies were included in the review. Most articles (n = 52, 66%) derived HUVs using the EQ-5D. Patients with advanced-stage breast cancer (range, 0.08 to 0.82) reported lower HUVs as compared with patients with early-stage breast cancer (range, 0.58 to 0.99). The meta-regression analysis found that undergoing chemotherapy and surgery and radiation, being diagnosed with an advanced stage of breast cancer, and recurrent cancer were associated with lower HUVs. The members of the general public reported lower HUVs as compared with patients. LIMITATIONS: There was considerable heterogeneity in the study population, health states assessed, and utility elicitation methods. CONCLUSION: This review provides a catalog of published HUVs related to breast cancer. The substantial heterogeneity in the health utility studies makes it challenging for researchers to choose which HUVs to use in cost-utility analyses for breast cancer interventions.

Obesity Modulates the Gut Microbiome in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer. Obesity is associated with increased incidence and worse prognosis in TNBC through various potential mechanisms. Recent evidence suggests that the gut microbiome plays a central role in the progression of cancer, and that imbalances or dysbiosis in the population of commensal microbiota can lead to inflammation and contribute to tumor progression. Obesity is characterized by low-grade inflammation, and gut dysbiosis is associated with obesity, chronic inflammation, and failure of cancer immunotherapy. However, the debate on what constitutes a "healthy" gut microbiome is ongoing, and the connection among the gut microbiome, obesity, and TNBC has not yet been addressed. This study aims to characterize the role of obesity in modulating the gut microbiome in a syngeneic mouse model of TNBC. 16S rRNA sequencing and metagenomic analyses were performed to analyze and annotate genus and taxonomic profiles. Our results suggest that obesity decreases alpha diversity in the gut microbiome. Metagenomic analysis revealed that obesity was the only significant factor explaining the similarity of the bacterial communities according to their taxonomic profiles. In contrast to the analysis of taxonomic profiles, the analysis of variation of functional profiles suggested that obesity status, tumor presence, and the obesity-tumor interaction were significant in explaining the variation of profiles, with obesity having the strongest correlation. The presence of tumor modified the profiles to a greater extent in obese than in lean animals. Further research is warranted to understand the impact of the gut microbiome on TNBC progression and immunotherapy.

Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US 'Food and Drug Administration' is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans.

Infections associated with cardiac electronic implantable devices: economic perspectives and impact of the TYRX™ antibacterial envelope.

The occurrence of cardiac implantable electronic devices (CIED) infections and related adverse outcomes have an important financial impact on the healthcare system, with hospitalization length of stay (2-3 weeks on average) being the largest cost driver, including the cost of device system extraction and device replacement accounting for more than half of total costs. In the recent literature, the economic profile of the TYRX™ absorbable antibacterial envelope was analysed taking into account both randomized and non-randomized trial data. Economic analysis found that the envelope is associated with cost-effectiveness ratios below USA and European benchmarks in selected patients at increased risk of infection. Therefore, the TYRX™ envelope, by effectively reducing CIED infections, provides value according to the criteria of affordability currently adopted by USA and European healthcare systems.

Sex differences in gut microbiota modulation of aversive conditioning, open field activity, and basolateral amygdala dendritic spine density.

Gut microbiota influence numerous aspects of host biology, including brain structure and function. Growing evidence implicates gut microbiota in aversive conditioning and anxiety-related behaviors, but research has focused almost exclusively on males. To investigate whether effects of gut dysbiosis on aversive learning and memory differ by sex, adult female and male C57BL/6N mice were orally administered a moderate dose of nonabsorbable antimicrobial medications (ATMs: neomycin, bacitracin, and pimaricin) or a control over 10 days. Changes in gut microbiome composition were analyzed by 16S rRNA sequencing. Open field behavior, cued aversive learning, context recall, and cued recall were assessed. Following behavioral testing, the morphology of basolateral amygdala (BLA) principal neuron dendrites and spines was characterized. Results revealed that ATMs induced gut dysbiosis in both sexes, with stronger effects in females. ATMs also exerted sex-specific effects on behavior and neuroanatomy. Males were more susceptible than females to microbial modulation of locomotor activity and anxiety-like behavior. Females were more susceptible than males to ATM-induced impairments in aversive learning and cued recall. Context recall remained intact, as did dendritic structure of BLA principal neurons. However, ATMs exerted a sex-specific effect on spine density. A second experiment was conducted to isolate the effects of gut perturbation to cued recall. Extinction was also examined. Results revealed no effect of ATMs on cued recall or extinction, suggesting that gut dysbiosis preferentially impacts aversive learning. These data shed new light on how gut microbiota interact with sex to influence aversive conditioning, open field behavior, and BLA dendritic spine architecture.

Clinical outcomes following rhythm control for atrial fibrillation: is early better?

Introduction: An integral aspect of atrial fibrillation (AF) management involves better symptom control, incorporating a rate control, rhythm control, or a combination strategy. The 2020 ESC Guidelines suggest that rhythm control strategy should be recommended for symptomatic patients, to mitigate their symptoms and improve the quality of life. However, adequately powered randomized control trials and prospective 'real-world' registries are needed to fully assess the impact of early rhythm control strategies on clinical outcomes in patients with AF.Objective: In this narrative review, we discuss clinical outcomes following rhythm management approach among patients with AF, considering the effectiveness of an early intervention strategy.Expert opinion: Patients involvement and shared decision-making are crucial when deciding the optimal management strategy among patients with AF. For those with newly diagnosed symptomatic AF, an early invasive approach such as catheter ablation may have a role in preventing AF progression and subsequent pathophysiological changes.

Cardiac Electronic Devices: Future Directions and Challenges.

Cardiovascular implantable electronic devices (CIEDs) are essential management options for patients with brady- and tachyarrhythmias or heart failure with concomitant optimal pharmacotherapy. Despite increasing technological advances, there are still gaps in the management of CIED patients, eg, the growing number of lead- and pocket-related long-term complications, including cardiac device-related infective endocarditis, requires the greatest care. Likewise, patients with CIEDs should be monitored remotely as a part of a comprehensive, holistic management approach. In addition, novel technologies used in smartwatches may be a convenient tool for long-term atrial fibrillation (AF) screening, especially in high-risk populations. Early detection of AF may reduce the risk of stroke and other AF-related complications. The objective of this review article was to provide an overview of novel technologies in cardiac rhythm-management devices and future challenges related to CIEDs.

Evaluation of the Anti-Tumor Activity of the Humanized Monoclonal Antibody NEO-201 in Preclinical Models of Ovarian Cancer.

Purpose: Despite high initial response rates with cytoreductive surgery, conventional chemotherapy and the incorporation of biologic agents, ovarian cancer patients often relapse and die from their disease. New approaches are needed to improve patient outcomes. This study was designed to evaluate the antitumor activity of NEO-201 monoclonal antibody (mAb) in preclinical models of ovarian cancer where the NEO-201 target is highly expressed. Experimental Design: Functional analysis of NEO-201 against tumor cell lines was performed by antibody-dependent cellular cytotoxicity (ADCC) assays. Binding of NEO-201 to tumor tissues and cell lines were determined by immunohistochemistry (IHC) and flow cytometry, respectively. Further characterization of the antigen recognized by NEO-201 was performed by mass spectrometry. Ovarian cancer models were used to evaluate the anti-tumor activity of NEO-201 in vivo. NEO-201 at a concentration of 250 g/mouse was injected intraperitoneally (IP) on days 1, 4, and 8. Human PBMCs were injected IP simultaneously as effector cells. Results: Both IHC and flow cytometry revealed that NEO-201 binds prominently to the colon, pancreatic, and mucinous ovarian cancer tissues and cell lines. Immunoprecipitation of the antigen recognized by NEO-201 was performed in human ovarian, colon, and pancreatic cancer cell lines. From these screening, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 were identified as the most likely targets of NEO-201. Our results confirmed that NEO-201 binds different types of cancers; the binding is highly selective for the tumor cells without cross reactivity with the surrounding healthy tissue. Functional analysis revealed that NEO-201 mediates ADCC killing against human ovarian and colorectal carcinoma cell lines in vitro. In addition, NEO-201 inhibited tumor growth in the presence of activated human PBMCs in orthotopic mouse models of both primary and metastatic ovarian cancer. Importantly, NEO-201 prolonged survival of tumor-bearing mice. Conclusions: These data suggested that NEO-201 has an antitumor activity against tumor cells expressing its antigen. Targeting an antigen expressed in tumors, but not in normal tissues, allows patient selection for optimal treatment. These findings strongly indicate that NEO-201 warrants clinical testing as both a novel therapeutic and diagnostic agent for treatment of ovarian carcinomas. A first in human clinical trial evaluating NEO-201 in adults with chemo-resistant solid tumors is ongoing at the NIH clinical Center.

The Monoclonal Antibody NEO-201 Enhances Natural Killer Cell Cytotoxicity Against Tumor Cells Through Blockade of the Inhibitory CEACAM5/CEACAM1 Immune Checkpoint Pathway.

Background: Natural killer (NK) cells are essential to innate immunity and participate in cancer immune surveillance. Heterophilic interactions between carcinoembryonic antigen (CEA) on tumor cells and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) on NK cells inhibit NK cell cytotoxicity against tumor cells. NEO-201 is a humanized IgG1 monoclonal antibody that recognizes members of CEACAM family, expressed specifically on a variety of human carcinoma cell lines and tumor tissues. This investigation was designed to determine whether the binding of NEO-201 with CEACAM5 on tumor cells can block the CEACAM5/CEACAM1 interaction to restore antitumor cytotoxicity of NK cells. Materials and Methods: In vitro functional assays, using various human tumor cell lines as target cells and NK-92 cells as effectors, were conducted to assess the ability of NEO-201 to block the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to enhance the in vitro killing of tumor cells by NK-92. NK-92 cells were used as a model of direct NK killing of tumor cells because they lack antibody-dependent cellular cytotoxicity activity. Results: Expression profiling revealed that various human carcinoma cell lines expressed different levels of CEACAM5+ and NEO-201+ cells. Addition of NEO-201 significantly enhanced NK-92 cell cytotoxicity against highly CEACAM5+/NEO-201+ expressing tumor cells, suggesting that its activity is correlated with the level of CEACAM5+/NEO-201+ expression. Conclusions: These findings demonstrate that NEO-201 can block the interaction between CEACAM5 on tumor cells and CEACAM1 on NK cells to reverse CEACAM1-dependent inhibition of NK cytotoxicity.

Three-year outcomes of Descemet's stripping endothelial keratoplasty in eyes with pre-existing glaucoma drainage devices.

BACKGROUND: Descemet's stripping endothelial keratoplasty (DSEK) is the most common procedure for corneal transplantation. The effect of a pre-existing glaucoma drainage device on long-term surgical outcomes is uncertain. METHODS: A retrospective chart review of all DSEK cases at an academic hospital over a 10-year period was conducted. RESULTS: 37 eyes who had undergone DSEK were included for analysis. These consist of 12 eyes with pre-existing GDD (GDD group), 13 eyes with glaucoma but no previous GDD (no-GDD group), and a control group of 12 patients with no ocular comorbidities apart from the indication for DSEK (control group). Visual acuity (VA) was significantly improved amongst all 3 groups, and there was no significant difference in VA between the GDD and no-GDD groups. There were no significant differences in absolute or increase in IOP between all three groups at 3 years. Graft survival rates of the 3 groups were not significantly different at 12 months. However, at 36 months, graft survival was 63% in the GDD group compared to 81% in the no-GDD group and 92% in the control group. In the GDD group, an increase in number of preoperative glaucoma drops, and a tube location in the anterior chamber were associated with an increased hazard ratio for failure. CONCLUSIONS: Presence of a GDD adversely affects graft survival whereas glaucomatous eyes which were medically managed or surgically managed without a GDD had survival rates comparable to controls. Glaucoma-filtering surgeries may confer graft survival advantage over tube shunt surgeries after DSEK.

Case Series of Combined iStent Implantation and Phacoemulsification in Eyes with Primary Angle Closure Disease: One-Year Outcomes.

PURPOSE: To evaluate the safety and efficacy of combined iStent® trabecular micro-bypass device (Glaukos, Laguna Hills, CA) and phacoemulsification in eyes with primary angle closure disease. METHODS: A two-center prospective interventional case series of consecutive patients with primary angle closure (PAC) or primary angle closure glaucoma (PACG) on at least one glaucoma medication, who underwent iStent implantation with cataract surgery. Postoperatively, patients were assessed on days 1 and 7, and months 1, 3, 6, and 12. The intraocular pressure (IOP), glaucoma medication use, visual acuity, and the presence of complications were assessed at each visit. Complete success was defined as IOP reduction of at least 20% without the use of glaucoma medications. RESULTS: Thirty-seven eyes with angle closure disease were included in this study. At 1-year, postoperative mean IOP (14.8 ± 3.94 mmHg) was significantly decreased compared with preoperative medicated (17.5 ± 3.82 mmHg, p = 0.008) and unmedicated (24.6 ± 3.41 mmHg, p < 0.001) IOP. Complete success was achieved in 89.2% of the eyes. The number of glaucoma medications decreased from 1.49 ± 0.77 to 0.14 ± 0.48 (p < 0.001). Preoperative medicated IOP was a risk factor for failure (hazard ratio 3.45, 95% confidence interval 1.52-7.85, p = 0.003), after adjustment for age, gender, and race. The most common postoperative complications were iStent occlusion with iris (27.0%) and hyphema (18.9%). There were no sight-threatening intraoperative or postoperative complications. CONCLUSION: Combined iStent implantation with cataract surgery was effective in lowering the IOP and the number of glaucoma medications for at least 12 months, with a favorable safety profile. FUNDING: Glaukos Corporation; NMRC Science Translational and Applied Research (STAR) award.

An IL-15 Superagonist, ALT-803, Enhances Antibody-Dependent Cell-Mediated Cytotoxicity Elicited by the Monoclonal Antibody NEO-201 Against Human Carcinoma Cells.

BACKGROUND: A major mechanism of action for therapeutic antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC). ALT-803 is an interleukin-15 superagonist complex that enhances ADCC against human carcinoma cells in vitro and exerts an antitumor activity in murine, rat, and human carcinomas in vivo. The authors investigated the ability of ALT-803 to modulate ADCC mediated by the humanized IgG1 monoclonal antibody (mAb) NEO-201 against human carcinoma cells. MATERIALS AND METHODS: ALT-803 modulating activity on ADCC mediated by NEO-201 was evaluated on several NEO-201 ligand-expressing human carcinoma cells. Purified human natural killer (NK) cells from multiple healthy donors were treated with ALT-803 before their use as effectors in ADCC assay. Modulation of NK cell phenotype and cytotoxic function by exposure to ALT-803 was evaluated by flow cytometry and gene expression analysis. RESULTS: ALT-803 significantly enhanced ADCC mediated by NEO-201. ALT-803 also upregulated NK activating receptors, antiapoptotic factors, and factors involved in the NK cytotoxicity, as well as downregulated gene expression of NK inhibiting receptors. CONCLUSIONS: These findings indicate that ALT-803 can enhance ADCC activity mediated by NEO-201, by modulating NK activation and cytotoxicity, suggesting a possible clinical use of ALT-803 in combination with NEO-201 for the treatment of human carcinomas.

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer.

The complex signaling networks of the tumor microenvironment that facilitate tumor growth and progression toward metastatic disease are becoming a focus of potential therapeutic options. The chemokine IL-8 is overexpressed in multiple cancer types, including triple-negative breast cancer (TNBC), where it promotes the acquisition of mesenchymal features, stemness, resistance to therapies, and the recruitment of immune-suppressive cells to the tumor site. The present study explores the utility of a clinical-stage monoclonal antibody that neutralizes IL-8 (HuMax-IL8) as a potential therapeutic option for TNBC. HuMax-IL8 was shown to revert mesenchymalization in claudin-low TNBC models both in vitro and in vivo as well as to significantly decrease the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) at the tumor site, an effect substantiated when used in combination with docetaxel. In addition, HuMax-IL8 enhanced the susceptibility of claudin-low breast cancer cells to immune-mediated lysis with NK and antigen-specific T cells in vitro. These results demonstrate the multifaceted way in which neutralizing this single chemokine reverts mesenchymalization, decreases recruitment of MDSCs at the tumor site, assists in immune-mediated killing, and forms the rationale for using HuMax-IL8 in combination with chemotherapy or immune-based therapies for the treatment of TNBC.

A novel bifunctional anti-PD-L1/TGF-ß Trap fusion protein (M7824) efficiently reverts mesenchymalization of human lung cancer cells.

Mesenchymalization is a cellular and molecular program in which epithelial cells progressively lose their well-differentiated phenotype and adopt mesenchymal characteristics. Tumor mesenchymalization occurs during the progression of cancer to metastatic disease, and is also associated with resistance to multiple therapeutics, including killing by cytotoxic immune cells. Furthermore, tumor cells can evade immune destruction by upregulating the checkpoint molecule PD-L1, and emerging research has found higher PD-L1 expression in mesenchymalized tumors. Here, the association between TGF-ß1-mediated mesenchymalization and PD-L1 was investigated in non-small cell lung cancer cells (NSCLC). TGF-ß1 was found to upregulate PD-L1 gene transcription in a Smad2-dependent manner, and a positive association between PD-L1 and phosphorylated Smad2 was found in NSCLC tumors. The potential to target these 2 negative immune regulators with a single agent was investigated using M7824, a novel clinical-stage bifunctional agent that targets both PD-L1 and TGF-ß. Treatment of NSCLC cells with M7824 in vitro and in vivo attenuated features of TGF-ß1-mediated mesenchymalization, including mesenchymal marker expression, proliferation suppression, and chemoresistance. These findings demonstrate that upregulation of tumor cell PD-L1 is a novel mechanism of TGF-ß1-induced immunosuppression in NSCLC, and that treatment with M7824 has the potential to simultaneously block both tumor mesenchymalization and PD-L1-dependent immunosuppression.