Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of antitumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is a member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized. In this study, we show that NRP2 is expressed during macrophage differentiation, is induced by tumor cells, and regulates phagocytosis in macrophages. Furthermore, NRP2 in TAM promoted efferocytosis and facilitated tumor growth. Deletion of NRP2 from TAM impaired the clearance of apoptotic tumor cells and increased secondary necrosis within tumors. This resulted in a break in the immune tolerance and reinitiated antitumor immune responses, characterized by robust infiltration of CD8 T and natural killer cells. This result suggests NRP2 may act as a molecular mediator that connects efferocytosis and immune suppression. Deletion of NRP2 in TAM downregulated several immunosuppressive and tumor-promoting genes and upregulated immunostimulatory genes in the myeloid compartment. Taken together, our study demonstrates that TAM-derived NRP2 plays a crucial role in tumor promotion through efferocytosis, opening the enticing option for the development of effective immunotherapy targeting TAM. Neuropilin-2 in macrophages promotes tumor growth by regulating efferocytosis of apoptotic tumor cells and orchestrating immune suppression. http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg .

Background The benefit of extracorporeal membrane oxygenation (ECMO) for patients with severe acute respiratory distress from COVID-19 refractory to medical management and lung-protective mechanical ventilation has not been adequately determined. Methods We reviewed the clinical course of 37 patients with laboratory-confirmed SARS-CoV-2 infection supported by venovenous ECMO at four ECMO referral centers within a large healthcare system. Patient characteristics, progression of hemodynamics and inflammatory markers, and clinical outcomes were evaluated. Results The patients had median age of 51 years (interquartile range [IQR] 40-59), and 73% were male. Peak plateau pressures, vasopressor requirements, and arterial PaCO 2 all improved with ECMO support. In our patient population, 24/37 patients (64.8%) survived to decannulation and 21/37 patients (56.8%) survived to discharge. Among patients discharged alive from the ECMO facility, 12 patients were discharged to a long-term acute care or rehabilitation facility, 2 were transferred back to the referring hospital for ventilatory weaning, and 7 were discharged directly home. For patients who were successfully decannulated, median length of time on ECMO was 17 days (IQR 10-33.5). Conclusions Venovenous ECMO represents a useful therapy for patients with refractory severe acute respiratory distress syndrome from COVID-19.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality in the United States. As much as 50-60% of CRC patients develop resistance to 5-fluorouracil (5FU)-based chemotherapeutic regimens, attributing the increased overall morbidity and mortality. In view of the growing evidence that active principles in various naturally-occurring botanicals can facilitate chemosensitization in cancer cells, herein, we undertook a comprehensive effort in interrogating the activity of one such botanical – andrographis – by analyzing its activity in CRC cell lines (both sensitive and 5FU-resistant; 5FUR), a xenograft animal model and patient-derived tumor organoids. We observed that combined treatment with andrographis was synergistic and resulted in a significant and dose-dependent increase in the efficacy of 5FU in HCT116 and SW480 5FUR cells (p&0.05), reduced clonogenic formation (p&0.01) and increased rates of caspase-9 mediated apoptosis (p&0.05). The genomewide expression analysis in cell lines led us to uncover that activation of ferroptosis and suppression of β-catenin/Wnt-signaling pathways were the key mediators for the anti-cancer and chemosensitizing effects of andrographis. Subsequently, we validated our findings in a xenograft animal model, as well as two independent CRC patient-derived organoids – which confirmed that combined treatment with andrographis was significantly more effective than 5FU and andrographis alone, and that these effects were in part orchestrated through dysregulated expression of key genes (including HMOX1, GCLC, GCLM and TCF7L2) within the ferroptosis and Wnt-signaling pathways. Collectively, our data highlight that andrographis might offer a safe and inexpensive adjunctive therapeutic option in the management of colorectal cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC.Experimental Design: The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n ¼ 163) transcriptomic data. This was followed by independent validation of the gene signature in the International Cancer Genome Consortium (ICGC, n ¼ 95), E-MTAB-6134 (n ¼ 288), and GSE71729 (n ¼ 123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate Cox regression analysis.Results: Our biomarker discovery effort identified a 15-gene immune, stromal, and proliferation (ISP) gene signature that significantly associated with poor OS [HR, 3.90; 95% confidence interval (CI), 2.36-6.41; P < 0.0001]. This signature also robustly predicted survival in three independent validation cohorts ICGC [HR,); P < 0.0001], E-MTAB-6134 [HR, 1.53 (1.14-2.04); P ¼ 0.004], and GSE71729 [HR, 2.33 (1.49-3.63); P < 0.0001]. Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all four cohorts; TCGA (AUC ¼ 0.94), ICGC (AUC ¼ 0.91), E-MTAB-6134 (AUC ¼ 0.80), and GSE71729 (AUC ¼ 0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort [n ¼ 119; HR, 2.62 (1.50-4.56); P ¼ 0.0004]. A nomogram was established which included the ISP, CA19-9, and T-and N-stage for eventual clinical translation.Conclusions: We report a novel gene signature for riskstratification and robust identification of patients with PDAC with poor molecular subtypes.