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February 3-5, 2016 | Lansdowne Resort, Leesburg, VA
Giorgio Trinchieri, MD
Cancer and Inflammation Program
Center for Cancer Research, NCI, NIH, Bethesda MD
Modulating chronic inflammation and the
microbiota for cancer prevention and therapy
Humans are metaorganisms
(symbionts) composed of host and microbial cells
(the microbiota).
Their cross-talk regulates many physiological functions including inflammation and
immunity.
Nature Magazine - 14 June 2012
Stomach cancer(Helicobacter pylori)
Colon rectal carcinoma(Escherichia coli, Fusobacterium spp. enterotoxigenic Bacteroides fragilis)
Gallbladder carcinoma(Salmonella enterica Thyphi)
[Oncogenic viruses, parasites]
Tumors
Malt lymphomaHepatocellular carcinoma
Mammary carcinomaThymic lymphoma
SarcomaOvarian Cancer
More than 16% of worldwide cancers are caused by infectious agents.
Cancer initiation, progression and response to immunotherapy and
chemotherapy
Local effects Systemic effects
Mets
Genomic mutations
Tumor promotion
Chronic inflammation
(infections, aseptic)
Intrinsic / oncogene induced
inflammation
Predisposing conditions (obesity, metabolic syndrome)
Cancer associated
inflammation
Tumor growth
Angiogenesis
Tissue remodeling Infiltration and
Metastasis
Immuno evasion
Co-morbidities
Response to therapy
Anti-cancer immune response
Primary tumor
Inflammation and immunity, caused by infectious agents or aseptic damage, affect cancer initiation, progression and response to therapy.
Serhan, C.N., N. Chiang, and J. Dalli. 2015. The resolution code of acute
inflammation: Novel pro-resolving lipid mediators in resolution. Semin.
Immunol. 27:200-215.SPM: specialized pro-resolving mediators
Great progress has been made in the characterization of therapeutic compounds with anti-inflammatory activity
or facilitating the resolution of inflammation
Chronic therapy with low dose acetylsalicylic acid (aspirin) that inhibits COX2 and induces the Resolvin D1 has been shown to significantly prevent different types of cancer although with significant toxicity
Aspirin and salicylic acid have been shown to be competitive inhibitors of ATP binding to IκB kinase-β.
Acetylsalicylic acid(Aspirin)
Salicylic acid Salsalate
4-8 g/d75 mg/d
COX1COX2
Non-steroidal anti-inflammatory drug (NSAID)
COX-2 inhibitors
NF-kB
//upload.wikimedia.org/wikipedia/commons/1/15/Salsalate.png//upload.wikimedia.org/wikipedia/commons/1/15/Salsalate.png//upload.wikimedia.org/wikipedia/commons/d/dc/Acetylsalicyls%C3%A4ure2.svg//upload.wikimedia.org/wikipedia/commons/d/dc/Acetylsalicyls%C3%A4ure2.svg//upload.wikimedia.org/wikipedia/commons/b/b5/Salicylic_Acid.svg//upload.wikimedia.org/wikipedia/commons/b/b5/Salicylic_Acid.svg
Resolvin D1 → FPR2
COX-2
Mechanisms underlying the anti-inflammatory effects of Aspirin
Chronic treatment with low doses Aspirin may be associated with significant toxicity
September/October 2015
The U.S. Preventive Service Task Force has recently issued a draft recommendation for the use of Aspirin in adult aged 50 to 69 to
prevent cardiovascular diseases and cancer
COMMENSAL MICROBIOTA Mets
Genomic mutations
Tumor promotion
Chronic inflammation
(infections, aseptic)
Intrinsic / oncogene induced
inflammation
Predisposing conditions (obesity, metabolic syndrome)
Cancer associated
inflammation
Tumor growth
Angiogenesis
Tissue remodeling Infiltration and
Metastasis
Immuno evasion
Co-morbidities
Response to therapy
Anti-cancer immune response
Primary tumor
The composition of the commensal microbiota modulates the effect of inflammation on tumor initiation, progression and response to therapy
Tumor
ROS
Oxaliplatin
CpG-ODN TNFVetizou M, Pitt JM, Daillere R, Lepage P, WaldschmittN, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S et al. (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350: 1079-84
Bacteroides such as B. thetaiotaomicron and B. fragilis allow anti-CTLA4 anti-tumor effect but are protective against colitis.
Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML, Chang EB, Gajewski TF (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350: 1084-9
CHALLENGE 1: Cancer and cancer co-morbidity prevention
Toxicity:On Target (mechanism-based)Off-targetHypersensitivity and immunological
Microbiota D Anti-tumor mechanisms
Microbiota E
Microbiota APro-carcinogenic
Tumor immunity
Microbiota B Cancer co-morbidities (Cachexia)
Microbiota CTumor immunity
Anti-carcinogenic
CHALLENGE 2: To enhance cancer therapy while controlling toxicity
Cancer as a disease of the metaorganism
P53-/K-ras* autochthonous sarcoma EL4 subcutaneous tumor
Oxaliplatin
Antibiotics +Oxaliplatin
Noriho Iida, Amiran Dzutsev, C. Andrew Stewart, ……… Giorgio Trinchieri, Romina S. Goldszmid Commensal bacteria control cancer response to therapy by modulating the tumor microenvironmentScience, 2013; 342:967-70
Rutkowski ….. Conejo-Garcia JRMicrobially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammationCancer Cell. 2015;27:27-40
Gut commensal microbiota signaling through TLR5 is needed for K-ras*/p53-/-
induced carcinogenesis and tumor growth
The effectiveness of immunotherapy with platinum compounds requires the
presence of the gut commensal microbiota
Medicine’s battlefield strategy:Human body as a battleground
Freely adapted from ideas expressed by Costello et al. Science 336:1255 (2012)
Cancer as a disease of the human metaorganism
TUMOR (cancer genetics)Intrinsic (oncogen mediated) inflammation
Extrinsic inflammationMicroenvironment
Innate and adaptive immune response(Immune contexture
Immunoscore)
GutMicrobiota
TUMOR
Medicine as park management:Humans as habitat (targeted removal of invasive, restoration, promotion of native species)
Cancer as a disease of the human metaorganism
Tumor microenvironmentInflammation
Innate and adaptive immune response
CommensalMicrobiota
TUMOR
Environmental and lifestyle factors
Host genetics
[Oncogene (Ras, Ret, Src)-induced]
intrinsic inflammation
Passenger/driver mutationsas tumor neoantigens
TUMOR CELLS(cancer genetics)
Bissell MJ, Hines WC (2011) Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17: 320-9
Dolberg DS, Bissell MJ (1984) Inability of Rous sarcoma virus to cause sarcomas in the avian embryo. Nature 309: 552-6
Dolberg DS, Hollingsworth R, Hertle M, Bissell MJ (1985) Wounding and its role in RSV-mediated tumor formation. Science 230: 676-8
Rous Sarcoma Virus
Rous Sarcoma Virus induces tumors in adult birdsat the site of injection or injury but not in sterileembryos even if the cells in the embryo expressthe Src viral oncogene and show a transformedphenotype when cultured in vitro.
Martincorena I, Roshan A, Gerstung M, Ellis P, Van Loo P, McLaren S, Wedge DC, Fullam A, Alexandrov LB, Tubio JM, Stebbings L, Menzies A, Widaa S, Stratton MR, Jones PH, Campbell PJ (2015) Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348: 880-6
Sun-induced somatic mutations in normal skin
In aged sun-exposed eyelid skin, over a quarter ofthe cells carry clonally expressed cancer-causingdriver mutations similar to those found insquamous cell carcinoma while maintaining thephysiological functions of normal skin withoutevolving in cancer.
Changes in our microbiota…
Antibiotics
Lifestyle Nutrition Hygiene
Infections
Dysbiosis: a microbiota imbalance that may be
associated with illnesses
Host Genetics
Probiotics
Age
Mode of delivery
Geographical location
https://www.google.com/url?q=https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?genetics&sa=U&ei=kPwoU4SfOMO90gGP7YDYDA&ved=0CEMQ9QEwCw&sig2=HmvITl6nHBlmD4yqIYy-fA&usg=AFQjCNHbk9AYCMlJi0i4jo9sK5M8CyLCDghttps://www.google.com/url?q=https://www.michaeljfox.org/understanding-parkinsons/living-with-pd/topic.php?genetics&sa=U&ei=kPwoU4SfOMO90gGP7YDYDA&ved=0CEMQ9QEwCw&sig2=HmvITl6nHBlmD4yqIYy-fA&usg=AFQjCNHbk9AYCMlJi0i4jo9sK5M8CyLCDghttp://www.n3inc.com/blog/wp-content/uploads/2012/12/probiotic-box.jpghttp://www.n3inc.com/blog/wp-content/uploads/2012/12/probiotic-box.jpghttp://wordlesstech.com/2013/12/27/natural-chemical-reverse-aging/http://wordlesstech.com/2013/12/27/natural-chemical-reverse-aging/
Interventions to reverse dysbiosis
• Antibiotics
• Probiotics: live microrganisms not constituent of the host microbiota but conferring a health benefit
• Prebiotics: nondigestible food components that favor the growth of beneficial members of the gut microbial community
• Fecal microbiota transplant
• Oral administration of pills containing bacterial spores with defined composition
Humans have co-evolved with microbial partners
We are a composite of species: bacteria, archea, protozoa, fungi, viruses, bacteriophages
Commensal microorganisms
• inhabit all barrier surfaces of our organism
• outnumber the human cells by about 3-10 fold
• their DNA (the microbiome) contains 100 times more genes than our ‘own’ human genome
Vagina
Stomach
Oesophagus
Mouth
Skin
Colon
FirmicutesBacteroidetesActinobacteriaProteobacteriaOther phyla
Cancer initiation, progression and
response to therapy
Metaorganismfunctions regulated by the host-commensal
cross-talk:
Metabolism
Cardiovascular, Excretory,
Musculoskeletal,and Adipose tissue
functions
Neurological. behavioral
and cognitive functions
Aging
Hematopoiesis
Circadian rhythm
Inflammation and Immunity
The human metaorganism
Both microbial and human cells act as sensors for
environmental changes, exchanging information and
adaptive responses.
Environmental factors
FoodChemicals
TemperatureRadiation
Physical and psycological
stressPathogens
………