Publications by authors named "Penghui Zhou"

37 Publications

Fucoidan-Supplemented Diet Potentiates Immune Checkpoint Blockage by Enhancing Antitumor Immunity.

Front Cell Dev Biol 2021 9;9:733246. Epub 2021 Aug 9.

Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong, China.

Immune checkpoint blockade (ICB) therapies such as PD-1 antibodies have produced significant clinical responses in treating a variety of human malignancies, yet only a subset of cancer patients benefit from such therapy. To improve the ICB efficacy, combinations with additional therapeutics were under intensive investigation. Recently, special dietary compositions that can lower the cancer risk or inhibit cancer progression have drawn significant attention, although few were reported to show synergistic effects with ICB therapies. Interestingly, Fucoidan is naturally derived from edible brown algae and exhibits antitumor and immunomodulatory activities. Here we discover that fucoidan-supplemented diet significantly improves the antitumor activities of PD-1 antibodies . Specifically, fucoidan as a dietary ingredient strongly inhibits tumor growth when co-administrated with PD-1 antibodies, which effects can be further strengthened when fucoidan is applied before PD-1 treatments. Immune analysis revealed that fucoidan consistently promotes the activation of tumor-infiltrating CD8 T cells, which support the evident synergies with ICB therapies. RNAseq analysis suggested that the JAK-STAT pathway is critical for fucoidan to enhance the effector function of CD8 T cells, which could be otherwise attenuated by disruption of the T-cell receptor (TCR)/CD3 complex on the cell surface. Mechanistically, fucoidan interacts with this complex and augments TCR-mediated signaling that cooperate with the JAK-STAT pathway to stimulate T cell activation. Taken together, we demonstrated that fucoidan is a promising dietary supplement combined with ICB therapies to treat malignancies, and dissected an underappreciated mechanism for fucoidan-elicited immunomodulatory effects in cancer.
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http://dx.doi.org/10.3389/fcell.2021.733246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382313PMC
August 2021

Mevalonate Blockade in Cancer Cells Triggers CLEC9A Dendritic Cell-Mediated Antitumor Immunity.

Cancer Res 2021 Sep 15;81(17):4514-4528. Epub 2021 Jul 15.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)-mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells. MVA pathway blockade or Rac1 knockdown in tumor cells induced CD8 T-cell-mediated antitumor immunity in immunocompetent mice but not in mice lacking CLEC9A dendritic cells. These findings demonstrate tumor MVA metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton, illustrating a new immune surveillance mechanism by which dendritic cells monitor tumor metabolic dysregulation and providing insight into how MVA pathway inhibition may potentiate anticancer immunity. SIGNIFICANCE: These findings suggest that mevalonate blockade in cancer cells disrupts Rac1 prenylation to increase recognition and cross-presentation by conventional dendritic cells, suggesting this axis as a potential target for cancer immunotherapy.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3977DOI Listing
September 2021

The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer.

Front Immunol 2021 2;12:689132. Epub 2021 Jun 2.

State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.
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http://dx.doi.org/10.3389/fimmu.2021.689132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206805PMC
June 2021

Modulation of lactate-lysosome axis in dendritic cells by clotrimazole potentiates antitumor immunity.

J Immunother Cancer 2021 05;9(5)

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Background: Dendritic cells (DCs) play a critical role in antitumor immunity, but the therapeutic efficacy of DC-mediated cancer vaccine remains low, partly due to unsustainable DC function in tumor antigen presentation. Thus, identifying drugs that could enhance DC-based antitumor immunity and uncovering the underlying mechanism may provide new therapeutic options for cancer immunotherapy.

Methods: In vitro antigen presentation assay was used for DC-modulating drug screening. The function of DC and T cells was measured by flow cytometry, ELISA, or qPCR. B16, MC38, CT26 tumor models and C57BL/6, Balb/c, nude, and mice were used to analyze the in vivo therapy efficacy and impact on tumor immune microenvironment by clotrimazole treatment.

Results: By screening a group of small molecule inhibitors and the US Food and Drug Administration (FDA)-approved drugs, we identified that clotrimazole, an antifungal drug, could promote DC-mediated antigen presentation and enhance T cell response. Mechanistically, clotrimazole acted on hexokinase 2 to regulate lactate metabolic production and enhanced the lysosome pathway and expression in DCs subsequently induced DC maturation and T cell activation. Importantly, in vivo clotrimazole administration induced intratumor immune infiltration and inhibited tumor growth depending on both DCs and CD8+ T cells and potentiated the antitumor efficacy of anti-PD1 antibody.

Conclusions: Our findings showed that clotrimazole could trigger DC activation via the lactate-lysosome axis to promote antigen cross-presentation and could be used as a potential combination therapy approach to improving the therapeutic efficacy of anti-PD1 immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-002155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141455PMC
May 2021

Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer.

J Immunother Cancer 2021 03;9(3)

Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China

Background: Dickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.

Methods: Tumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.

Results: Elevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.

Conclusions: DKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.
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http://dx.doi.org/10.1136/jitc-2020-001498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009229PMC
March 2021

COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas.

Cell 2021 04 3;184(7):1895-1913.e19. Epub 2021 Feb 3.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China.

A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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http://dx.doi.org/10.1016/j.cell.2021.01.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857060PMC
April 2021

DGKA Mediates Resistance to PD-1 Blockade.

Cancer Immunol Res 2021 04 19;9(4):371-385. Epub 2021 Feb 19.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Immunologic checkpoint blockade has been proven effective in a variety of malignancies. However, high rates of resistance have substantially hindered its clinical use. Understanding the underlying mechanisms may lead to new strategies for improving therapeutic efficacy. Although a number of signaling pathways have been shown to be associated with tumor cell-mediated resistance to immunotherapy, T cell-intrinsic resistant mechanisms remain elusive. Here, we demonstrated that diacylglycerol kinase alpha (Dgka) mediated T-cell dysfunction during anti-PD-1 therapy by exacerbating the exhaustion of reinvigorated tumor-specific T cells. Pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed development of resistance to PD-1 blockade. Dgka inhibition also enhanced the efficacy of anti-PD-1 therapy. We further found that the expression of DGKA in cancer cells promoted tumor growth via the AKT signaling pathway, suggesting that DGKA might be a target in tumor cells as well. Together, these findings unveiled a molecular pathway mediating resistance to PD-1 blockade and provide a potential therapeutic strategy with combination immunotherapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0216DOI Listing
April 2021

Role of PRDM1 in Tumor Immunity and Drug Response: A Pan-Cancer Analysis.

Front Pharmacol 2020 15;11:593195. Epub 2020 Dec 15.

Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

PR domain zinc finger protein 1 (PRDM1) is a regulator of both B cell and T cell differentiation and plays a critical role in immunosuppression. Its role in tumor immunity and correlation with drug response remain unknown. This work comprehensively analyzed the transcriptional expression pattern of the PRDM1 among 33 types of malignancies from The Cancer Genome Atlas and the Genotype-Tissue Expression projects. Besides, correlation of the PRDM1 with cancer prognosis, immune infiltrates, checkpoint markers, cancer stemness and drug response were explored. High expression level of PRDM1 were observed in ACC, COAD, LAML, LGG, LUAD, OV, PAAD, STAD, TGCT. Cox regression model showed high expression of PRDM1 in tumor samples correlates with poor prognosis in LGG, PAAD, UVM while favorable prognosis in KIRC, SKCM and THCA. PRDM1 expression positively correlates with the expression of LAG3, CTLA4, PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), TIGIT in the majority of 33 cancer types. PRDM1 positively correlated with TNFRSF14 in LGG and UVM among cancers with unfavorable prognosis; this correlation were weak or even negative in cancers with favorable prognosis. The top negatively enriched KEGG terms in high PRDM1 subgroup were B cell receptor signaling, T cell receptor signaling, and the top negatively enriched HALLMARK terms included IL-2-STAT5 signaling and allograft rejection. The expression of PRDM1 was found positively correlated with cancer stemness in CHOL, KIRP, TGCT, THYM and UVM. A series of targeted drugs and small-molecule drugs with promising efficacy predicted by PRDM1 level were identified. The clinical significance and biological impact of high transcriptional expression of PRDM1 differs across different cancers. Inhibiting the PRDM1-dependent signaling could be a novel and promising strategy of immunotherapy in cancers including LGG, PAAD and UVM.
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http://dx.doi.org/10.3389/fphar.2020.593195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770985PMC
December 2020

High-affinity neoantigens correlate with better prognosis and trigger potent antihepatocellular carcinoma (HCC) activity by activating CD39CD8 T cells.

Gut 2021 Oct 1;70(10):1965-1977. Epub 2020 Dec 1.

Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China

Objective: It remains controversial whether tumour mutational burden (TMB) or neoantigens are prognostic markers in hepatocellular carcinoma (HCC). This study aimed to define the function of TMB or neoantigens in antitumour immunotherapy.

Design: Neoantigens of patients (n=56) were analysed by pVAC tools with major histocompatibility complex-1 (MHC-I) algorithms based on whole exome sequencing and neoantigens with mutant type IC <50 nM were defined as high-affinity neoantigens (HANs). Patients were segregated into HAN-high/low groups by median of HAN value, and overall survival (OS) was analysed. Autologous organoid killing model was developed to clarify the antitumour activity of HANs.

Results: The value of HAN showed a better correlation with OS (=0.0199) than TMB (=0.7505) or neoantigens (=0.2297) in patients with HCC and positively correlated with the frequency of CD39CD8 tumour infiltrating lymphocytes (TILs). Furthermore, HAN-specific CD8 T cells were identified in CD39CD8 TILs, which showed better antitumour activity in HAN-high versus HAN-low group. In addition, more effective HAN peptides were identified in HAN-high versus HAN-low group. Besides, flow cytometry data showed that in fresh tumour, CD39PD-1CD8 TILs displayed an effector phenotype and stronger antitumour activity in HAN-high versus HAN-low group. More importantly, patients in HAN-high versus HAN-low group showed a better prognosis after anti-PD-1 therapy.

Conclusions: Our study first demonstrates that HAN value positively correlates with better OS in patients with HCC. HANs trigger antitumour activity by activating tumour-reactive CD39CD8 T cells, and patients in HAN-high group benefited more from anti-PD-1 therapy than HAN-low group. These findings may provide a novel strategy for personalised antitumour therapies for HCC.
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http://dx.doi.org/10.1136/gutjnl-2020-322196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458084PMC
October 2021

Epidemiological Analysis of Coronavirus Disease 2019 (COVID-19) in 2 Cities in China Based on Public Data.

Disaster Med Public Health Prep 2020 Oct 26:1-5. Epub 2020 Oct 26.

Tianjin Center for Disease Control and Prevention, Tianjin, China.

Based on the public data from the health departments of Tianjin and Shenzhen, we conducted a comparative analysis of the coronavirus disease 2019 (COVID-19) epidemic situation between these 2 cities. The aim of this study was to evaluate the role of public data in epidemic prevention and control of COVID-19, providing a scientific advice for the subsequent mitigation and containment of COVID-19 prevalence.
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http://dx.doi.org/10.1017/dmp.2020.401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884672PMC
October 2020

Dysregulated adaptive immune response contributes to severe COVID-19.

Cell Res 2020 09 5;30(9):814-816. Epub 2020 Aug 5.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.

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http://dx.doi.org/10.1038/s41422-020-0391-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403569PMC
September 2020

Blocking interaction between SHP2 and PD-1 denotes a novel opportunity for developing PD-1 inhibitors.

EMBO Mol Med 2020 06 11;12(6):e11571. Epub 2020 May 11.

MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangzhou, China.

Small molecular PD-1 inhibitors are lacking in current immuno-oncology clinic. PD-1/PD-L1 antibody inhibitors currently approved for clinical usage block interaction between PD-L1 and PD-1 to enhance cytotoxicity of CD8 cytotoxic T lymphocyte (CTL). Whether other steps along the PD-1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA-approved chemical for treating methemoglobinemia, potently inhibits PD-1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine-secreting activity of CTL inhibited by PD-1. Mechanistically, MB blocks interaction between Y248-phosphorylated immunoreceptor tyrosine-based switch motif (ITSM) of human PD-1 and SHP2. MB enables activated CTL to shrink PD-L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD-1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA-approved chemical capable of potently inhibiting the function of PD-1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD-1 signaling axis.
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http://dx.doi.org/10.15252/emmm.201911571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278553PMC
June 2020

Chimeric antigen receptor-modified T-cell therapy for platelet-derived growth factor receptor α-positive rhabdomyosarcoma.

Cancer 2020 May;126 Suppl 9:2093-2100

Melanoma and Sarcoma Medical Oncology Unit, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: New immunotherapeutic approaches are urgently needed for metastatic rhabdomyosarcoma, which is associated with poor survival and unsatisfactory treatment outcomes. Platelet-derived growth factor receptor α (PDGFRA) plays an essential role in the onset and development of rhabdomyosarcoma and is a new potential therapeutic target for rhabdomyosarcoma. The objective of this study was to generate humanized PDGFRA single-chain variable fragment-based chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) against PDGFRA-positive rhabdomyosarcoma.

Methods: PDGFRA antigen expression was evaluated in specimens from patients with rhabdomyosarcoma. CAR-T cells containing a PDGFRA-specific single-chain variable fragment was developed in combination with a 4-1BB costimulatory domain and a CD3-ζ signaling domain. Specific cytotoxic effects of PDGFRA CAR-T cells, T-cell proliferation, and cytokine secretion were investigated in vitro and in vivo.

Results: PDGFRA CAR-T cells produced large amounts of immune-promoting cytokines, including interleukin 2, tumor necrosis factor α, and interferon γ, and exhibited efficient cytotoxic activity toward human PDGFRA-overexpressing rhabdomyosarcoma cells in vitro. In a subcutaneous xenograft model, CAR-T cells were more effective against PDGFRA-overexpressing rhabdomyosarcoma than against rhabdomyosarcoma with low PDGFRA expression in terms of tumor regression and patient survival. Expanded CAR-T cells also were detected in peripheral blood.

Conclusions: The current study demonstrates for the first time that the PDGFRA antigen is a promising target for CAR-T-cell therapy in rhabdomyosarcoma and likely in a wide spectrum of other PDGFRA-expressing cancers.
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http://dx.doi.org/10.1002/cncr.32764DOI Listing
May 2020

Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies.

Cancers (Basel) 2020 Jan 24;12(2). Epub 2020 Jan 24.

Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland Baltimore School of Medicine, Baltimore, MD 21201, USA.

Background: CTLA-4 was the first immune checkpoint targeted for cancer therapy and the first target validated by the FDA (Food and Drug Administration) after approval of the anti-CTLA-4 antibody, Ipilimumab. However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies. As a result, the effort to target CTLA-4 for cancer immunotherapy has stagnated. To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment. Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP). A major unresolved issue is how to select appropriate cancer types for future clinical development.

Methods: We generated a landscape of the immune tumor microenvironment from RNAseq and genomic data of 7279 independent cancer samples belonging to 22 cancer types from The Cancer Genomics Atlas (TCGA) database. Based primarily on genomic and RNAseq data from pre-treatment clinical samples of melanoma patients who were later identified as responders and nonresponders to the anti-CTLA-4 antibody Ipilimumab, we identified 5 ranking components of responsiveness to anti-CTLA-4, including CTLA-4 gene expression, ADCC potential, mutation burden, as well as gene enrichment and cellular composition that favor CTLA-4 responsiveness. The total ranking number was calculated by the sum of 5 independent partitioning values, each comprised of 1-3 components.

Results: Our analyses predict metastatic melanoma as the most responsive cancer, as expected. Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies. Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg.

Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies. Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies. The comprehensive ranking of major cancer types provides a roadmap for clinical development of the next generation of anti-CTLA-4 antibodies.
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http://dx.doi.org/10.3390/cancers12020284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073233PMC
January 2020

A Feedback Circuitry between Polycomb Signaling and Fructose-1, 6-Bisphosphatase Enables Hepatic and Renal Tumorigenesis.

Cancer Res 2020 02 16;80(4):675-688. Epub 2020 Jan 16.

Program of Cancer Research, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.

Suppression of gluconeogenesis elevates glycolysis and is commonly observed in tumors derived from gluconeogenic tissues including liver and kidney, yet the definitive regulatory mechanism remains elusive. Here, we screened an array of transcription regulators and identified the enhancer of zeste homolog 2 (EZH2) as a key factor that inhibits gluconeogenesis in cancer cells. Specifically, EZH2 repressed the expression of a rate-limiting gluconeogenic enzyme fructose-1, 6-bisphosphatase 1 (FBP1) and promoted tumor growth primarily through FBP1 suppression. Furthermore, EZH2 was upregulated by genotoxins that commonly induce hepatic and renal tumorigenesis. Genotoxin treatments augmented EZH2 acetylation, leading to reduced association between EZH2 and its E3 ubiquitin ligase SMURF2. Consequently, EZH2 became less ubiquitinated and more stabilized, promoting FBP1 attenuation and tumor formation. Intriguingly, FBP1 physically interacted with EZH2, competed for EZH2 binding, and dissembled the polycomb complex. Therefore, FBP1 suppresses polycomb-initiated transcriptional responses and constitutes a double-negative feedback loop indispensable for EZH2-promoted tumorigenesis. Finally, EZH2 and FBP1 levels were inversely correlated in tumor tissues and accurately predicted patient survival. This work reveals an unexpected cross-talk between epigenetic and metabolic events, and identifies a new feedback circuitry that highlights EZH2 inhibitors as liver and kidney cancer therapeutics. SIGNIFICANCE: A novel feedback loop involving EZH2 and suppression of the gluconeogenesis enzyme FBP1 promotes hepatocellular cancer growth..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2060DOI Listing
February 2020

Multifactorial Deep Learning Reveals Pan-Cancer Genomic Tumor Clusters with Distinct Immunogenomic Landscape and Response to Immunotherapy.

Clin Cancer Res 2020 06 7;26(12):2908-2920. Epub 2020 Jan 7.

Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Purpose: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers.

Experimental Design: We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy.

Results: Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden.

Conclusions: Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299824PMC
June 2020

Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity.

Nat Med 2019 09 9;25(9):1428-1441. Epub 2019 Sep 9.

Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-γ T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.
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http://dx.doi.org/10.1038/s41591-019-0566-4DOI Listing
September 2019

cGAS/STING axis mediates a topoisomerase II inhibitor-induced tumor immunogenicity.

J Clin Invest 2019 08 13;129(11):4850-4862. Epub 2019 Aug 13.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death (ICD)-inducing drugs available that can kill cancer cells, enhance tumor immunogenicity, increase the in vivo immune infiltration, and thereby boosting a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immuno-stimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still investigational. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and T cell activation assay. We identified that teniposide, a DNA topoisomerase II inhibitor, could induce high mobility group box 1 (HMGB1) release and type I interferon signaling in tumor cells, and teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling including NF-κB activation and STING-dependent type I interferon signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 on multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity, and enabled a potential chemo-immunotherapeutic approach to potentiate the therapeutic efficacy of anti-PD1 immunotherapy.
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http://dx.doi.org/10.1172/JCI127471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819145PMC
August 2019

Melatonin synergizes BRAF-targeting agent vemurafenib in melanoma treatment by inhibiting iNOS/hTERT signaling and cancer-stem cell traits.

J Exp Clin Cancer Res 2019 Feb 4;38(1):48. Epub 2019 Feb 4.

State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China.

Background: As the selective inhibitor of BRAF kinase, vemurafenib exhibits effective antitumor activities in patients with V600 BRAF mutant melanomas. However, acquired drug resistance invariably develops after its initial treatment.

Methods: Immunohistochemical staining was performed to detect the expression of iNOS and hTERT, p-p65, Epcam, CD44, PCNA in mice with melanoma xenografts. The proliferation and migration of melanoma cells were detected by MTT, tumorsphere culture, cell cycle, cell apoptosis, AO/EB assay and colony formation, transwell assay and scratch assay in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the iNOS/hTERT signaling pathways were detected by western blot. Nucleus-cytoplasm separation, and immunofluorescence analyses were conducted to explore the location of p50/p65 in melanoma cell lines. Flow cytometry assay were performed to determine the expression of CD44. Pull down assay and ChIP assay were performed to detect the binding ability of p65 at iNOS and hTERT promoters. Additionally, hTERT promoter-driven luciferase plasmids were transfected in to melanoma cells with indicated treatment to determine luciferase activity of hTERT.

Results: Melatonin significantly and synergistically enhanced vemurafenib-mediated inhibitions of proliferation, colony formation, migration and invasion and promoted vemurafenib-induced apoptosis, cell cycle arresting and stemness weakening in melanoma cells. Further mechanism study revealed that melatonin enhanced the antitumor effect of vemurafenib by abrogating nucleus translocation of NF-κB p50/p65 and their binding at iNOS and hTERT promoters, thereby suppressing the expression of iNOS and hTERT. The elevated anti-tumor capacity of vemurafenib upon co-treatment with melatonin was also evaluated and confirmed in mice with melanoma xenografts.

Conclusions: Collectively, our results demonstrate melatonin synergizes the antitumor effect of vemurafenib in human melanoma by inhibiting cell proliferation and cancer-stem cell traits via targeting NF-κB/iNOS/hTERT signaling pathway, and suggest the potential of melatonin in antagonizing the toxicity of vemurafenib and augmenting its sensitivities in melanoma treatment.
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http://dx.doi.org/10.1186/s13046-019-1036-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360719PMC
February 2019

FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells.

Nature 2018 12 28;564(7734):130-135. Epub 2018 Nov 28.

State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Dysfunctional T cells in the tumour microenvironment have abnormally high expression of PD-1 and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer. The clinical success of these inhibitors highlights the need to study the mechanisms by which PD-1 is regulated. Here we report a mechanism of PD-1 degradation and the importance of this mechanism in anti-tumour immunity in preclinical models. We show that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells. FBXO38 is an E3 ligase of PD-1 that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and CD28 signalling, but led to faster tumour progression in mice owing to higher levels of PD-1 in tumour-infiltrating T cells. Anti-PD-1 therapy normalized the effect of FBXO38 deficiency on tumour growth in mice, which suggests that PD-1 is the primary target of FBXO38 in T cells. In human tumour tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescued Fbxo38 transcription and therefore downregulated PD-1 levels in PD-1 T cells in mice. These data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway.
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http://dx.doi.org/10.1038/s41586-018-0756-0DOI Listing
December 2018

Increased vessel perfusion predicts the efficacy of immune checkpoint blockade.

J Clin Invest 2018 05 16;128(5):2104-2115. Epub 2018 Apr 16.

Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, and.

Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8+ T cell depletion, IFN-γ neutralization, or implantation of tumors in IFN-γ receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8+ T cell accumulation and IFN-γ production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.
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http://dx.doi.org/10.1172/JCI96582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957454PMC
May 2018

Detection of Viruses and Mycoplasma pneumoniae in Hospitalized Patients with Severe Acute Respiratory Infection in Northern China, 2015-2016.

Jpn J Infect Dis 2018 Mar 28;71(2):134-139. Epub 2018 Feb 28.

Department of Infectious Disease Control, Tianjin Centers for Disease Control and Prevention.

Severe acute respiratory infection (SARI) presents a huge disease and economic burden worldwide. The present study described the frequency and types of different infectious etiologies among hospitalized patients with SARI in Tianjin, China, during 2015 and 2016. Basic information, in addition to a throat or serum sample, was collected from SARI patients. Nine viruses were detected using reverse transcription polymerase chain reaction, and Mycoplasma pneumoniae was detected using the Serodia Myco II gelatin particle agglutination test. A total of 585 specimens from 2,290 SARI cases were collected. The most common infection (19.66%, 115/585) was M. pneumoniae, followed by influenza virus A/B (6.15%, 36/585), and respiratory syncytial virus (4.96%, 29/585). Identification of viral or M. pneumoniae infections was the highest in the pediatric medicine ward (74.84%, 119/159), followed by the intensive care unit (37.04%, 80/216) and respiratory medicine ward (34.29%, 72/210). M. pneumoniae was highest (38.71%, 24/62) in the 5-14-year age group. Influenza was the main infection in January 2015 and March 2016. The correlation coefficient for the proportion of hospitalized cases of SARI and the positive detection rate within the same week was 0.25. M. pneumoniae and influenza were the leading pathogens among hospitalized SARI patients. A continued surveillance of hospitalized cases of SARI can detect emerging diseases, such as avian influenza A (H7N9) virus and other respiratory disease outbreaks.
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http://dx.doi.org/10.7883/yoken.JJID.2017.412DOI Listing
March 2018

CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia.

J Hematol Oncol 2018 01 10;11(1). Epub 2018 Jan 10.

State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.

Background: Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment.

Methods: We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells.

Results: The CLL-1 CAR-T cells specifically lysed CLL-1 cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1 myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression.

Conclusions: CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.
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http://dx.doi.org/10.1186/s13045-017-0553-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761206PMC
January 2018

New Approaches in CAR-T Cell Immunotherapy for Breast Cancer.

Adv Exp Med Biol 2017 ;1026:371-381

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.

Despite significant advances in surgery, chemotherapy, radiotherapy, endocrine therapy, and molecular-targeted therapy, breast cancer remains the leading cause of death from malignant tumors among women. Immunotherapy has recently become a critical component of breast cancer treatment with encouraging activity and mild safety profiles. CAR-T therapy using genetically modifying T cells with chimeric antigen receptors (CAR) is the most commonly used approach to generate tumor-specific T cells. It has shown good curative effect for a variety of malignant diseases, especially for hematological malignancies. In this review, we briefly introduce the history and the present state of CAR research. Then we discuss the barriers of solid tumors for CARs application and possible strategies to improve therapeutic response with a focus on breast cancer. At last, we outlook the future directions of CAR-T therapy including managing toxicities and developing universal CAR-T cells.
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http://dx.doi.org/10.1007/978-981-10-6020-5_17DOI Listing
July 2018

Twin defects engineered Pd cocatalyst on CN nanosheets for enhanced photocatalytic performance in CO reduction reaction.

Nanotechnology 2017 Dec;28(48):484003

Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang, 321004, People's Republic of China.

Photocatalytic conversion of CO to value-added chemicals, a potential route to addressing the depletion of fossil fuels and anthropogenic climate change, is greatly limited by the low-efficient semiconductor photocatalyst. The integration of cocatalyst with light-harvesting semiconductor is a promising approach to enhancing the photocatalytic performance in CO reduction reaction. The enhancement is greatly determined by the catalytic active sites on the surface of cocatalyst. Herein, we demonstrate that the photocatalytic performance in the CO reduction reaction is greatly promoted by twin defects engineered Pd cocatalyst. In this work, Pd nanoicosahedrons with twin defects were in situ grown on CN nanosheets, which effectively improve the photocatalytic performance in reduction of CO to CO and CH in comparison with Pd nanotetrahedrons without twin defects. It is proposed that the twin boundary (TB) terminations on the surface of Pd cocatalysts are highly catalytic active sites for CO reduction reaction. Based on the proposed mechanism, the photocatalytic activity and selectivity in CO reduction were further advanced through reducing the size of Pd icosahedral cocatalyst resulted from the increased surface density of TB terminations. The defect engineering on the surface of cocatalyst represents a novel route in realizing high-performance photocatalytic applications.
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http://dx.doi.org/10.1088/1361-6528/aa9137DOI Listing
December 2017

Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.

Nature 2016 Mar 16;531(7596):651-5. Epub 2016 Mar 16.

State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.
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http://dx.doi.org/10.1038/nature17412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431PMC
March 2016

Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation.

Nat Commun 2015 Jan 20;6:5909. Epub 2015 Jan 20.

Center for Cancer and Immunology Research and Division of Pathology, Children's Research Institute, Children's National Medical Center, Washington DC 20010, USA.

CD24 is overexpressed in nearly 70% human cancers, whereas TP53 is the most frequently mutated tumour-suppressor gene that functions in a context-dependent manner. Here we show that both targeted mutation and short hairpin RNA (shRNA) silencing of CD24 retard the growth, progression and metastasis of prostate cancer. CD24 competitively inhibits ARF binding to NPM, resulting in decreased ARF, increase MDM2 and decrease levels of p53 and the p53 target p21/CDKN1A. CD24 silencing prevents functional inactivation of p53 by both somatic mutation and viral oncogenes, including the SV40 large T antigen and human papilloma virus 16 E6-antigen. In support of the functional interaction between CD24 and p53, in silico analyses reveal that TP53 mutates at a higher rate among glioma and prostate cancer samples with higher CD24 mRNA levels. These data provide a general mechanism for functional inactivation of ARF and reveal an important cellular context for genetic and viral inactivation of TP53.
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http://dx.doi.org/10.1038/ncomms6909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300525PMC
January 2015

Discovering cancer immunotherapy targets in vivo.

Oncoimmunology 2014;3:e28500. Epub 2014 Apr 17.

Dana-Farber Cancer Institute; Boston, MA USA ; Program in Immunology; Harvard Medical School; Boston, MA USA.

A key challenge facing the cancer immunology field is the discovery of the most suitable targets for therapeutic intervention. We recently reported a novel RNA-interference (RNAi)-based approach for systematic discovery of such targets in the tumor microenvironment in vivo utilizing pooled shRNA libraries as a screening tool. Here, we discuss applying this unbiased method to develop innovative cancer therapeutics.
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http://dx.doi.org/10.4161/onci.28500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063151PMC
February 2021

[Study on the correlation between serum lipid and serum carnitine palmitoyl transferase 1A in rural adults over 40 years in Tianjin].

Wei Sheng Yan Jiu 2014 Mar;43(2):228-32

Objective: To explore the status of serum lipids and analyze its relationship with carnitine palmitoyl transferase 1A (CPT1 A) in rural people over 40 in Tianjin, China.

Methods: By cluster multi-stratified sample of 719 people over 40 was investigated with a questionnaire from rural areas in Tianjin. And finally draw a conclusion based on data analysis from fasting blood and measured total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and CPT1 A.

Results: In this research, the rate of dyslipidemia was 46.73%, in which 48.22 percent male and 45.41 percent female, a nonsignificant difference. CPT1 A correlated with TC, LDL-C were 0.123 and 0.130, with simple linear regression, and there was only significant difference between LDL-C and CPT1 A by multiple regression analysis.

Conclusion: There is a high rate of dyslipidemia among the rural people over the age of 40 in Tianjin, and the CPT1 A is closely associated with serum lipid.
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March 2014

Disruption of CD8+ Treg activity results in expansion of T follicular helper cells and enhanced antitumor immunity.

Cancer Immunol Res 2014 Mar 31;2(3):207-16. Epub 2013 Dec 31.

Authors' Affiliations: Departments of Department of Gastroenterology, Hepatology, and Infectious Diseases, University of Düsseldorf, Düsseldorf, Germany.

Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs CD8 Treg suppressive activity. Here, we report that the growth of B16 melanoma is substantially delayed in these Qa-1-mutant mice after therapeutic immunization with B16 melanoma cells engineered to express granulocyte macrophage colony-stimulating factor compared with Qa-1 B6-WT controls. Reduced tumor growth is associated with enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8(+) T effectors compared with CD8 Tregs. These data suggest that the CD8(+) T effector-Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Tregs represents a potentially effective strategy to enhance antitumor immunity.
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http://dx.doi.org/10.1158/2326-6066.CIR-13-0121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217219PMC
March 2014
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