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Table S1, Figure S1-S7

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)–associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.

Supplementary figures of CRC mice model, immune cell infiltration, function of MDSCs and T cells, proliferation of CRC cells, expression of RIPK3, COX-2, stat3, p-stat3, stat6, p-stat6, EP1-4, PKA, CREB, p-CREB, Arg-1, and PGE2 production

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Supplementary tables of human clinical characteristics of samples and database GSE17536

Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE2 receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer.Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg. Cancer Res; 78(19); 5586–99. ©2018 AACR.

Metabolic reprogramming is critical for the polarization and function of tumor-associated macrophages (TAM) and hepatocarcinogenesis, but how this reprogramming occurs is unknown. Here, we showed that receptor-interacting protein kinase 3 (RIPK3), a central factor in necroptosis, is downregulated in hepatocellular carcinoma (HCC)–associated macrophages, which correlated with tumorigenesis and enhanced the accumulation and polarization of M2 TAMs. Mechanistically, RIPK3 deficiency in TAMs reduced reactive oxygen species and significantly inhibited caspase1-mediated cleavage of PPAR. These effects enabled PPAR activation and facilitated fatty acid metabolism, including fatty acid oxidation (FAO), and induced M2 polarization in the tumor microenvironment. RIPK3 upregulation or FAO blockade reversed the immunosuppressive activity of TAMs and dampened HCC tumorigenesis. Our findings provide molecular basis for the regulation of RIPK3-mediated, lipid metabolic reprogramming of TAMs, thus highlighting a potential strategy for targeting the immunometabolism of HCC.

Lipid metabolic reprogramming plays an essential role in regulating the progression of colorectal cancer (CRC). However, the effect of lysophosphatidic acid (LPA) metabolism on CRC development is incompletely characterized. Here, we compared the mRNA levels of human CRC tissues to those of paracarcinoma tissues and focused on the notably enriched LPA metabolic pathways. We identified and verified that 1-acylglycerol-3-phosphate O-acyltransferase 4 (Agpat4) was aberrantly expressed in CRC tissues and predicted poor survival in CRC patients. Manipulating Agpat4 expression in CRC cells did not affect the growth or migration of CRC cells in vitro, whereas Agpat4 silencing suppressed CRC cell growth in subcutaneous and peritoneal xenograft models. Mechanistically, Agpat4 silencing-induced LPA release from CRC cells and polarized macrophages to an M1-like phenotype through LPA receptors 1 and 3. This M1 activation, characterized by elevated p38/p65 signaling and increased proinflammatory cytokines, promoted the infiltration and activation of CD4+ and CD8+ T cells in the tumor microenvironment. Modulation of the Agpat4/LPA/p38/p65 axis regulated macrophage polarization, T-cell activity and CRC progression. Notably, combined therapy with LPA and regular chemotherapy drugs synergistically suppressed CRC development. Taken together, our results showed that the Agpat4/LPA axis in CRC cells regulated p38/p65 signaling-dependent macrophage polarization, T-cell activation, and CRC progression. The Agpat4/LPA/p38/p65 axis might represent a potential target for therapy in the clinic.

Metabolic reprogramming in tumor-associated macrophages (TAM) is associated with cancer development, however, the role of macrophage triglyceride metabolism in cancer metastasis is unclear. Here, we showed that TAMs exhibited heterogeneous expression of abhydrolase domain containing 5 (ABHD5), an activator of triglyceride hydrolysis, with migratory TAMs expressing lower levels of ABHD5 compared with the nonmigratory TAMs. ABHD5 expression in macrophages inhibited cancer cell migration in vitro in xenograft models and in genetic cancer models. The effects of macrophage ABHD5 on cancer cell migration were dissociated from its metabolic function as neither triglycerides nor ABHD5-regulated metabolites from macrophages affected cancer cell migration. Instead, ABHD5 deficiency in migrating macrophages promoted NFκB p65-dependent production of matrix metalloproteinases (MMP). ABHD5 expression negatively correlated with MMP expression in TAMs and was associated with better survival in patients with colorectal cancer. Taken together, our findings show that macrophage ABHD5 suppresses NFκB-dependent MMP production and cancer metastasis and may serve as a prognostic marker in colorectal cancer. Significance: These findings highlight the mechanism by which reduced expression of the metabolic enzyme ABHD5 in macrophages promotes cancer metastasis.

Key Points Question What are the long-term health outcomes associated with COVID-19 infection 1 year after hospital discharge? Findings In this cohort study of 2433 patients who had been hospitalized with COVID-19, the most common symptoms at 1 year after discharge were fatigue, sweating, chest tightness, anxiety, and myalgia. Patients with severe disease had more postinfection symptoms and higher chronic obstructive pulmonary disease assessment test scores. Meaning This study reported prolonged symptoms of COVID-19 and found that severe disease during hospitalization was a risk factor for more symptoms and higher chronic obstructive pulmonary disease assessment test scores., This cohort study investigates 1-year health outcomes and their associated risk factors among COVID-19 survivors in Wuhan, China., Importance The long-term health outcomes and symptom burden of COVID-19 remain largely unclear. Objective To evaluate health outcomes of COVID-19 survivors 1 year after hospital discharge and to identify associated risk factors. Design, Setting, and Participants This retrospective, multicenter cohort study was conducted at 2 designated hospitals, Huoshenshan Hospital and Taikang Tongji Hospital, both in Wuhan, China. All adult patients with COVID-19 discharged between February 12 and April 10, 2020, were screened for eligibility. Of a consecutive sample of 3988 discharged patients, 1555 were excluded (796 declined to participate and 759 were unable to be contacted) and the remaining 2433 patients were enrolled. All patients were interviewed via telephone from March 1 to March 20, 2021. Statistical analysis was performed from March 28 to April 18, 2021. Exposures COVID-19. Main Outcomes and Measures All patients participated in telephone interviews using a series of questionnaires for evaluation of symptoms, along with a chronic obstructive pulmonary disease (COPD) assessment test (CAT). Logistic regression models were used to evaluate risk factors for fatigue, dyspnea, symptom burden, or higher CAT scores. Results Of 2433 patients at 1-year follow-up, 1205 (49.5%) were men and 680 (27.9%) were categorized into the severe disease group as defined by the World Health Organization guideline; the median (IQR) age was 60.0 (49.0-68.0) years. In total, 1095 patients (45.0%) reported at least 1 symptom. The most common symptoms included fatigue, sweating, chest tightness, anxiety, and myalgia. Older age (odds ratio [OR], 1.02; 95% CI, 1.01-1.02; P

Background: 5-aza-2'-deoxycytidine (5Aza), a DNA methyltransferase (DNMT) inhibitor, could activate tumor adaptive immunity to inhibit tumor progression. However, the molecular mechanisms by which 5Aza regulates tumor immune microenvironment are still not fully understood. Methods: The role of 5Aza in immune microenvironment of peritoneal carcinomatosis (PC) of colorectal cancer (CRC) was investigated. The effects of 5Aza on macrophage activation were studied by flow cytometry, real-time PCR, Western blotting assays, and Drug Affinity Responsive Target Stability (DARTS). The effects of 5Aza on tumor immunity were validated in stromal macrophages and T cells from CRC patients. Results: 5Aza could stimulate the activation of macrophages toward an M1-like phenotype and subsequent activation of T cells in premetastatic fat tissues, and ultimately suppress CRC-PC in immune-competent mouse models. Mechanistically, 5Aza stimulated primary mouse macrophages toward to a M1-like phenotype characterized by the increase of p65 phosphorylation and IL-6 expression. Furthermore, we screened and identified ATP-binding cassette transporter A9 (ABC A9) as a binding target of 5Aza. 5Aza induced cholesterol accumulation, p65 phosphorylation and IL-6 expression in an ABC A9-dependent manner. Pharmacological inhibition of NF-κB, or genetic depletion of IL-6 abolished the antitumor effect of 5Aza in mice. In addition, the antitumor effect of 5Aza was synergistically potentiated by conventional chemotherapeutic drugs 5-Fu or OXP. Finally, we validated the reprogramming role of 5Aza in antitumor immunity in stromal macrophages and T cells from CRC patients. Conclusions: Taken together, our findings showed for the first time that 5Aza suppressed CRC-PC by regulating macrophage-dependent T cell activation in premetastatic microenvironment, meanwhile uncovered a DNA methylation-independent mechanism of 5Aza in regulating ABC A9-associated cholesterol metabolism and macrophage activation.

A schematic illustration is given regarding serine restriction on tumor growth. Once the cellular abundance of serine decreased or alanine accumulated, the serine palmitoyltransferase (SPT) alternatively conjugates alanine and palmitoyl-CoA to form 3-keto-intermediates, which is rapidly converted to 1-deoxysphinganine and further metabolized to 1-deoxydihydroceramide (1-DeoxyDHCER) and 1-deoxyceramide (1-DeoxyDHCER), so that to exert cytotoxicity for tumor suppression.

Colorectal cancer (CRC) usually gives rise to transcoelomic spread and ultimately causes peritoneal carcinomatosis (PC). However, mechanism studies, especially the immunological basis of colorectal PC, are rarely revealed due to lack of a suitable PC model. Here we selected a mouse colorectal cancer cell line MC-38 for intraperitoneal inoculation in the C57BL/6 mice to mimic the development of colorectal PC. We demonstrated that the injected CRC cells preferentially and rapidly migrated and colonized in the visceral fat tissues, but not in other visceral organs. With flow cytometric analysis, we found the proportions of spleen T cells and B cells were not affected by PC progression, while the ratios of blood CD4+ and CD8+ T cells were largely influenced. Especially, the quantity or activity of CD4+ and CD8+ T cells in visceral fats were intimately regulated by PC development. Taken together, we successfully constructed a colorectal PC model in immune-competent mice and revealed the alteration of adaptive immunity in PC development. Our study might potentiate the research and therapy strategies of colorectal PC.

Background: Long noncoding RNAs (lncRNAs) have been demonstrated to play essential roles in renal cell carcinoma (RCC). However, the role of lncRNA KCNQ1DN in RCC remains unclear. Methods: The expression of KCNQ1DN in RCC and the corresponding adjacent tissues was measured by qPCR. RNA fluorescence in situ hybridization (FISH) assay, methylation analysis, reporter gene assays and functional tests were performed to reveal the effects of KCNQ1DN on RCC. Results: In the present study, we found that lncRNA KCNQ1DN was notably decreased in RCC tissues and cell lines. RNA FISH assay showed that KCNQ1DN mainly localized to the cytoplasm. Methylation analysis revealed that the proximal region of KCNQ1DN promoter was hypermethylated in RCC tissues relative to the adjacent normal ones. Functional studies clarified that KCNQ1DN repressed the RCC cell growth and cell cycle progression. Mechanistically, KCNQ1DN inhibited the expression of c-Myc, which might further upregulate cyclin D1 and suppress p27 at mRNA and protein levels in RCC cells. Reporter gene assays revealed that the transcriptional activity of c-Myc promoter was inhibited by KCNQ1DN. The in vivo experiments in nude mice showed that KCNQ1DN overexpression dramatically repressed the growth of xenograft tumors and the expression of corresponding c-Myc. Conclusion: These results indicated that KCNQ1DN inhibit the growth of RCC cells in vitro and in vivo through repressing the oncogene c-myc, suggesting that KCNQ1DN may serve as a novel target for the treatment of RCC.

Macrophages are essential components of the immune system in tumors. It can be recruited and educated to two mainly polarized subpopulations (M1-like and M2-like) of tumor-associated macrophages (TAMs) to display anti-tumor or protumor function during the tumor occurrence and progression. Reprogramming of metabolism, especially lipid metabolism, is a typical characteristic of TAMs polarization, which was confirmed recently as a vital target for tumor therapy. However, the relationship between TAMs and lipid metabolism is still obscure in the past decade. In this review, we will first introduce the historical aspects of TAMs, and then discuss the correlation of main lipids (triglycerides, cholesterol, and phospholipids) to TAMs activation and summarize the mechanisms by which lipid metabolism mediated tumor escape the immunological surveillance as well as currently available drugs targeting these mechanisms. We hope that this chapter will give a better understanding of lipid metabolism in TAMs for those who are interested in this field, and lay a foundation to develop novel strategies for tumor therapy by targeting lipid metabolism.

Macrophages are essential components of the immune system in tumors. It can be recruited and educated to two mainly polarized subpopulations (M1-like and M2-like) of tumor-associated macrophages (TAMs) to display anti-tumor or protumor function during the tumor occurrence and progression. Reprogramming of metabolism, especially lipid metabolism, is a typical characteristic of TAMs polarization, which was confirmed recently as a vital target for tumor therapy. However, the relationship between TAMs and lipid metabolism is still obscure in the past decade. In this review, we will first introduce the historical aspects of TAMs, and then discuss the correlation of main lipids (triglycerides, cholesterol, and phospholipids) to TAMs activation and summarize the mechanisms by which lipid metabolism mediated tumor escape the immunological surveillance as well as currently available drugs targeting these mechanisms. We hope that this chapter will give a better understanding of lipid metabolism in TAMs for those who are interested in this field, and lay a foundation to develop novel strategies for tumor therapy by targeting lipid metabolism.

Pro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs., Adipose tissue macrophages are central to controlling inflammation in the context of obesity. Here the authors present a new infrared dye (IR-61) that accumulates in the mitochondria of these cells resulting in anti-inflammatory effects that counter obesity-associated pathology in mice.

Peritoneal carcinomatosis (PC) of colorectal cancer (CRC) is a terminal phase of malignancy with no effective strategies for the prevention of this condition. Here we established PC models in mice by intraperitoneal engraftment of CRC cells and revealed an unexpected role for a high-fat diet (HFD) in preventing metastatic seeding in the visceral fat. Mechanistically, the HFD stimulated the activation of adipose tissue macrophages (ATMs) toward an M1-like phenotype and enhanced ATM tumor phagocytosis in a TLR4-dependent manner. Furthermore, the TLR4–Cxcl10 axis in ATMs promoted T cell recruitment, and M1-like macrophages stimulated T cell activation in tumor-seeded fats. The inhibitory effect of the HFD on tumor seeding was abolished with the ablation of macrophages, inactivation of T cells, or blockade of the TLR4–Cxcl10 axis in macrophages. Finally, we showed that a HFD and conventional chemotherapeutic agents (oxaliplatin or 5-fluorouracil) synergistically improved the survival of tumor-seeded mice. Collectively, our findings demonstrate that peritoneal seeding of CRC can be suppressed by short-term treatment with a HFD in the early phase, providing a novel concept for the management of these patients in the clinic.

H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M-cells, tumors and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and TCA cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here we show H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing manners to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in pre-clinical models suggesting key therapeutic targets for much needed treatments.

SummaryBackgroundTo investigate the impact of goggles on their health and clinical practice during management of patients with COVID-19.Methods231 nurse practitioners were enrolled who worked in isolation region in designated hospitals to admit patients with COVID-19 in China. Demographic data, goggle-associated symptoms and underlying reasons, incidence of medical errors or exposures, the effects of fog in goggles on practice were all collected. Data were stratified and analyzed by age or working experience. Risk factors of goggle-associated medical errors were analyzed by multivariable logistical regression analysis.FindingsGoggle-associated symptoms and foggy goggles widely presented in nurses. The most common symptoms were headache, skin pressure injury and dizziness. Headache, vomit and nausea were significantly fewer reported in nurses with longer working experience while rash occurred higher in this group. The underlying reasons included tightness of goggles, unsuitable design and uncomfortable materials. The working status of nurses with more working experience was less impacted by goggles. 11.3% nurses occurred medical exposures in clinical practice while 19.5% nurses made medical errors on patients. The risk factors for medical errors were time interval before adapting to goggle-associated discomforts, adjusting goggles and headache.InterpretationGoggle-associated symptoms and fog can highly impact the working status and contribute to medical errors during management of COVID-19. Increased the experience with working in PPE through adequate training and psychological education may benefit for relieving some symptoms and improving working status. Improvement of goggle design during productive process was strongly suggested to reduce incidence of discomforts and medical errors.

Risk indicators viral load (ORF1ab Ct), lymphocyte percentage (LYM%), C-reactive protein (CRP), interleukin-6 (IL-6), procalcitonin (PCT) and lactic acid (LA) in COVID-19 patients have been proposed in recent studies. However, the predictive effects of those indicators on disease classification and prognosis remains largely unknown. We dynamically measured those reported indicators in 132 cases of COVID-19 patients including the moderate-cured (moderated and cured), severe-cured (severe and cured) and critically ill (died). Our data showed that CRP, PCT, IL-6, LYM%, lactic acid and viral load could predict prognosis and guide classification of COVID-19 patients in different degrees. CRP, IL-6 and LYM% were more effective than other three factors in predicting prognosis. For disease classification, CRP and LYM% were sensitive in identifying the types between critically ill and severe (or moderate). Notably, among the investigated factors, LYM% was the only one that could distinguish between the severe and moderate types. Collectively, we concluded that LYM% was the most sensitive and reliable predictor for disease typing and prognosis. During the COVID-19 pandemic, the precise classification and prognosis prediction are critical for saving the insufficient medical resources, stratified treatment and improving the survival rate of critically ill patients. We recommend that LYM% be used independently or in combination with other indicators in the management of COVID-19.

SUMMARYProlonged viral shedding is associated with severe status and poor prognosis of COVID-19 patients. Unexpectedly, here we report a non-severe patient with the longest duration of viral shedding. According to the investigation on the clinical and epidemiological information of this case, we concluded that this type of virus might have a low toxicity and transmissibility, but have a prolonged infective ability and was hardly to be eliminated in the body with regular therapy. However, infusion of plasma from recovered patients showed high efficiency in elimination of this virus. Our findings might shed light on the management of COVID-19.

Tumor microenvironment is a special environment for tumor survival, which is characterized by hypoxia, acidity, nutrient deficiency, and immunosuppression. The environment consists of the vasculature, immune cells, extracellular matrix, and proteins or metabolic molecules. A large number of recent studies have shown that not only tumor cells but also the immune cells in the tumor microenvironment have undergone metabolic reprogramming, which is closely related to tumor drug resistance and malignant progression. Tumor immunotherapy based on T cells gives patients new hope, but faces the dilemma of low response rate. New strategies sensitizing cancer immunotherapy are urgently needed. Metabolic reprogramming can directly affect the biological activity of tumor cells and also regulate the differentiation and activation of immune cells. The authors aim to review the characteristics of tumor microenvironment, the metabolic changes of tumor‐associated immune cells, and the regulatory role of metabolic reprogramming in cancer immunotherapy., Metabolic reprogramming is the basis of tumor microenvironment, which consists of cellular and extracellular components. The cellular components are mainly composed of hematopoietic immune cells (For example, TAMs, tumor‐associated macrophages; TILs, tumor‐infiltrated lymphocytes; TADCs, tumor‐associated dendritic cells; TANKs, tumor‐associated natural killer cells) and resident stromal cells. The extracellular components are mainly composed of extracellular matrix and cell‐secreted factors. The interaction between cancer cells and interstitial cells in the tumor microenvironment regulates tumorigenesis and progression.

SummaryBackgroundCoronavirus disease-2019 (COVID-19) is a rapidly escalating epidemic caused by SARS-CoV-2. Identification of a simple and effective indicator to assess disease severity and prognosis is urgently needed.MethodsDynamic changes of blood lymphocyte percentage (LYM%) in 15 death cases, 15 severe cases as well as 40 moderate cases of COVID-19 patients were retrospectively analyzed. A Time-LYM% model (TLM) was established according to the descriptive studies and was validated in 92 hospitalized cases.ResultsResults from death and severe cases showed that LYM% in blood tests were inversely associated with the severity and prognosis of COVID-19. LYM% in moderate type of patients with COVID-19 remained higher than 20% 10-12 days after symptom onset. In contrast, LYM% was lower than 20% in severe cases. However, LYM% in severe cases was higher than 5% 17-19 days after the onset of the disease, while it fell below 5% in death cases. Accordingly, we established a Time-LYM% model (TLM), which was validated as an independent criterion of disease classification in another 92 hospitalized patients with COVID-19.ConclusionLymphopenia can be used as an indicator of disease severity and prognosis of COVID-19 patients. TLM is worth of application in the clinical practice.

Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE2 receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer. Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg. Cancer Res; 78(19); 5586–99. ©2018 AACR.

Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy., Tumour associated macrophages (TAMs) have an altered lipid metabolism. Here the authors show that downregulation of monoacylglycerols lipase MGLL in TAMs induces lipid accumulation and tumor progression by polarizing TAMs toward tumor-promoting through activation of cannabinoid receptor CB2.

The effect of scientific training on course learning in undergraduates is still controversial. In this study, we investigated the academic performance of undergraduate students with and without scientific training. The results show that scientific training improves students' test scores in general medical courses, such as biochemistry and molecular biology, cell biology, physiology, and even English. We classified scientific training into four levels. We found that literature reading could significantly improve students' test scores in general courses. Students who received scientific training carried out experiments more effectively and published articles performed better than their untrained counterparts in biochemistry and molecular biology examinations. The questionnaire survey demonstrated that the trained students were more confident of their course learning, and displayed more interest, motivation and capability in course learning. In summary, undergraduate academic performance is improved by scientific training. Our findings shed light on the novel strategies in the management of undergraduate education in the medical school. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(5):379-384, 2017.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit(1,2). Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet(3–5) enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT–mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.