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

………