Trapping of Lipopolysaccharide to Promote Immunotherapy against Colorectal Cancer and Attenuate Liver Metastasis

The development and progression of colorectal cancer (CRC) is closely related to gut microbiome. Here, the impact of lipopolysaccharide (LPS), one of the most prevalent products in the gut microbiome, on CRC immunotherapy is investigated. It is found that LPS is abundant in orthotopic CRC tissue and is associated with low responses to anti‐PD‐L1 mAb therapy, and clearance of Gram‐negative bacteria from the gut using polymyxin B (PmB) or blockade of Toll‐like receptor 4 using TAK‐242 will both relieve the immunosuppressive microenvironment and boost T‐cell infiltration into the CRC tumor. Further, an engineered LPS‐targeting fusion protein is designed and its coding sequence is loaded into a lipid–protamine–DNA (LPD) nanoparticle system for selective expression of LPS trap protein and blocking LPS inside the tumor, and this nanotrapping system significantly relieves the immunosuppressive microenvironment and boosts anti‐PD‐L1 mAb therapy against CRC tumors. This LPS trap system even attenuates CRC liver metastasis when applied, suggesting the importance of blocking LPS in the gut–liver axis. The strategy applied here may provide a useful new way for treating CRC as well as other epithelial cancers that interact with mucosa microbiome.

[1]  Leaf Huang,et al.  Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap , 2018, Nature Communications.

[2]  Laurence Zitvogel,et al.  Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors , 2018, Science.

[3]  E. Le Chatelier,et al.  Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients , 2018, Science.

[4]  Riyue Bao,et al.  The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients , 2018, Science.

[5]  Donna Neuberg,et al.  Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer , 2017, Science.

[6]  Noam Shental,et al.  Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine , 2017, Science.

[7]  Leaf Huang,et al.  Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer. , 2017, ACS nano.

[8]  Ludmila V. Danilova,et al.  Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade , 2017, Science.

[9]  Fangfang Guo,et al.  Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy , 2017, Cell.

[10]  Rong Li,et al.  LPS-induced CXCR4-dependent migratory properties and a mesenchymal-like phenotype of colorectal cancer cells , 2017, Cell adhesion & migration.

[11]  Leaf Huang,et al.  Local and transient gene expression primes the liver to resist cancer metastasis , 2016, Science Translational Medicine.

[12]  J. Zhuang,et al.  Lipopolysaccharide increases the release of VEGF-C that enhances cell motility and promotes lymphangiogenesis and lymphatic metastasis through the TLR4- NF-κB/JNK pathways in colorectal cancer , 2016, Oncotarget.

[13]  M. Kiechle,et al.  CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer , 2016, British Journal of Cancer.

[14]  R. Teague,et al.  Adapting Cancer Immunotherapy Models for the Real World. , 2016, Trends in immunology.

[15]  Mari Mino-Kenudson,et al.  PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes , 2016, Modern Pathology.

[16]  Y. Nie,et al.  Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. , 2016, World journal of gastroenterology.

[17]  M. Belvin,et al.  MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. , 2016, Immunity.

[18]  Xiaoxiao Wang,et al.  Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade. , 2016, Cancer cell.

[19]  Axel Hoos,et al.  Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies , 2016, Nature Reviews Drug Discovery.

[20]  Jedd D. Wolchok,et al.  PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations , 2016, Science Translational Medicine.

[21]  R. Weissleder,et al.  Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. , 2016, Immunity.

[22]  Jason B. Williams,et al.  Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy , 2015, Science.

[23]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[24]  Erik Sahai,et al.  Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity , 2015, Cell.

[25]  Axel Hoos,et al.  Big opportunities for small molecules in immuno-oncology , 2015, Nature Reviews Drug Discovery.

[26]  Bert Vogelstein,et al.  PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. , 2015, The New England journal of medicine.

[27]  P. Sharma,et al.  Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential , 2015, Cell.

[28]  Hassan Razvi,et al.  The microbiome of the urinary tract—a role beyond infection , 2015, Nature Reviews Urology.

[29]  J. Castle,et al.  Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma , 2014, BMC Genomics.

[30]  Cynthia L Sears,et al.  Microbes, microbiota, and colon cancer. , 2014, Cell host & microbe.

[31]  F. Marincola,et al.  Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment , 2013, Science.

[32]  Eric Vivier,et al.  The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide , 2013, Science.

[33]  R. Schwabe,et al.  The Microbiome and Cancer , 2021, Gut Feelings.

[34]  C. A. Valencia,et al.  Tribody: robust self-assembled trimeric targeting ligands with high stability and significantly improved target-binding strength. , 2013, Biochemistry.

[35]  Yu Zhang,et al.  Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver , 2013, Clinical & Experimental Metastasis.

[36]  J. Galanko,et al.  Association of plasma endotoxin, inflammatory cytokines and risk of colorectal adenomas , 2013, BMC Cancer.

[37]  C. Datz,et al.  Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth , 2012, Nature.

[38]  Belgin Dogan,et al.  Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota , 2012, Science.

[39]  Raul Rabadan,et al.  Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. , 2012, Cancer cell.

[40]  D. Douek,et al.  Microbial translocation across the GI tract. , 2012, Annual review of immunology.

[41]  Richard A. Moore,et al.  Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. , 2012, Genome research.

[42]  George Coukos,et al.  Cancer immunotherapy comes of age , 2011, Nature.

[43]  J. Spicer,et al.  LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. , 2011, Cancer research.

[44]  N. Tsuchimori,et al.  TAK-242 (Resatorvid), a Small-Molecule Inhibitor of Toll-Like Receptor (TLR) 4 Signaling, Binds Selectively to TLR4 and Interferes with Interactions between TLR4 and Its Adaptor Molecules , 2011, Molecular Pharmacology.

[45]  Pnina Brodt,et al.  Systemic inflammation increases cancer cell adhesion to hepatic sinusoids by neutrophil mediated mechanisms , 2009, International journal of cancer.

[46]  R. Xu,et al.  Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. , 2007, Gastroenterology.

[47]  J. Wang,et al.  Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system , 2006, British Journal of Cancer.

[48]  K. Tanabe,et al.  Mouse models of subcutaneous spleen reservoir for multiple portal venous injections to treat liver malignancies. , 2005, Cancer research.

[49]  D. van der Waaij,et al.  The dose at which neomycin and polymyxin B can be applied for selective decontamination of the digestive tract in mice , 1980, Journal of Hygiene.

[50]  G. Szabo.  Gut-liver axis in alcoholic liver disease. , 2015, Gastroenterology.

[51]  E. Kuipers,et al.  Colorectal cancer , 2015, Nature Reviews Disease Primers.

[52]  Marco M. Domingues,et al.  Biophysical characterization of polymyxin B interaction with LPS aggregates and membrane model systems. , 2012, Biopolymers.