Innate Immunity and Inflammation

ISBTc ‐ Primer on Tumor Immunology and Biological Therapy of Cancer

InnateInnate ImmunityImmunity andand

InflammationInflammation

WillemWillem Overwijk,Overwijk, Ph.D.Ph.D. MDMD AndersonAnderson CancerCancer CenterCenter CenterCenter forfor CancerCancer ImmunologyImmunology ResearchResearch Houston,Houston, TXTX

www.allthingsbeautiful.com InnateInnate ImmunityImmunity andand InflammationInflammation

• Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications InnateInnate ImmunityImmunity andand InflammationInflammation

• Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications • Innate Immunity: Immunity that is naturally present and is not due to prior sensitization to an antigen; generally nonspecific. It is in contrast to acquired/adaptive immunity.

Adapted from Merriam‐Webster Medical Dictionary • Innate Immunity: Immunity that is naturally present and is not due to prior sensitization to an antigen; generally nonspecific. It is in contrast to acquired/adaptive immunity.

• Inflammation: a local response to tissue injury – Rubor (redness) – Calor (heat) – Dolor (pain) – Tumor (swelling)

Adapted from Merriam‐Webster Medical Dictionary ““InnateInnate ImmunityImmunity”” andand ““InflammationInflammation”” areare vaguevague termsterms

•• SpecificSpecific cellcell typestypes andand moleculesmolecules orchestrateorchestrate specificspecific typestypes ofof inflammationinflammation ““InnateInnate ImmunityImmunity”” andand ““InflammationInflammation”” areare vaguevague termsterms

•• SpecificSpecific cellcell typestypes andand moleculesmolecules orchestrateorchestrate specificspecific typestypes ofof inflammationinflammation

•• InnateInnate ImmunityImmunity AA ≠≠ InnateInnate ImmunityImmunity BB •• InflammationInflammation AA ≠≠ InflammationInflammation BB

CD4CD4++ TT cellcell

Zhou et al., Immunity, 2009 CD4CD4++ TT cell:cell: Th1Th1 oror Th2?Th2?

Zhou et al., Immunity, 2009 CD4CD4++ TT cell:cell: Th1Th1 oror Th2Th2 oror Th17Th17 oror

Th9Th9 oror TregTreg oror TfhTfh oror ??

Zhou et al., Immunity, 2009 Today,Today, thethe termterm ““CD4CD4++ TT cellcell”” cancan

meanmean manymany thingsthings

Zhou et al., Immunity, 2009 ““InnateInnate ImmunityImmunity”” andand ““InflammationInflammation”” cancan meanmean manymany thingsthings

•• SpecificSpecific cellcell typestypes andand moleculesmolecules orchestrateorchestrate specificspecific typestypes ofof inflammationinflammation

•• InnateInnate ImmunityImmunity AA ≠≠ InnateInnate ImmunityImmunity BB •• InflammationInflammation AA ≠≠ InflammationInflammation BB

•• SomeSome immuneimmune responsesresponses promotepromote cancer,cancer, othersothers suppresssuppress itit

InnateInnate ImmunityImmunity andand InflammationInflammation

Functions: • Rapid response to tissue damage • Limit spread of infection • Initiate adaptive immune response (T, B) • Initiate tissue repair InnateInnate ImmunityImmunity andand Inflammation:Inflammation: AA PaperPaper CutCut

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmunityImmunity andand Inflammation:Inflammation: AA PaperPaper CutCut

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmunityImmunity andand Inflammation:Inflammation: AA PaperPaper CutCut

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmunityImmunity andand Inflammation:Inflammation: AA PaperPaper CutCut

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmunityImmunity andand InflammationInflammation

• Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications InnateInnate ImmuneImmune Molecules:Molecules: CyclooxygenaseCyclooxygenase‐‐22 (COX(COX‐‐2)2)

Recognize • inflammation Cause • inflammation InnateInnate ImmuneImmune Molecules:Molecules: ComplementComplement SystemSystem Recognize • pathogens • antibodies • lectins Cause • pathogen clearance • chemotaxis • inflammation Janeway, Immunobiology, 7th Ed.

InnateInnate ImmuneImmune Molecules:Molecules: typetype II IFN(IFN(‐‐))

• Induced by infection/danger • Antiviral/Antiproliferative • Increase innate and adaptive immunity

• Cause inflammation InnateInnate ImmuneImmune CellsCells

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmuneImmune CellsCells

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmuneImmune CellsCells

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmuneImmune Cells:Cells: granulocytesgranulocytes

( )

Antigen Presentation

Recognize Cause • pathogens • pathogen clearance • antibodies • inflammation

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmuneImmune Cells:Cells: phagocytesphagocytes

Monocyte Blood Recognize precursor of tissue Macrophages and • pathogens Dendritic Cells • antibodies

Cause • pathogen clearance • adaptive immunity • inflammation

Janeway, Immunobiology, 7th Ed.

InnateInnate ImmuneImmune Cells:Cells: NK,NK, NKTNKT andand  TT cellscells

Recognize • pathogens • stressed cells • “altered self” Cause • pathogen clearance • stressed/abnormal cell clearance • inflammation DangerDanger signalssignals startstart inflammationinflammation PATHOGENS DAMAGE

Rubartelli & Lotze, Trends in Immunology 2007 DangerDanger signalssignals startstart inflammationinflammation PATHOGENS DAMAGE

Rubartelli & Lotze, Trends in Immunology 2007 ReceptorsReceptors sensesense Danger:Danger: PathogensPathogens

Kawai & Akira, Nat. Immunol. 2010 ReceptorsReceptors sensesense Danger:Danger: DamageDamage

Kawai & Akira, Nat. Immunol. 2010 InnateInnate ImmunityImmunity andand InflammationInflammation

• Outcomes vary:

‐ Promote cancer (Bad inflammation)

‐ Suppress cancer (Good inflammation)

InnateInnate ImmunityImmunity andand InflammationInflammation

• Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications BadBad InflammationInflammation CausesCauses CancerCancer

DANGER cellular damage caused by • pathogens • physical damage • chemicals • UV • etc IMMUNE RESPONSE DANGER INFLAMMATION IMMUNE RESPONSE DANGER INFLAMMATION COLLATERAL DAMAGE

IMMUNE RESPONSE DANGER INFLAMMATION COLLATERAL DAMAGE

IMMUNE RESPONSE INFLAMMATION COLLATERAL DAMAGE

IMMUNE RESPONSE DANGER INFLAMMATION COLLATERAL DAMAGE

CHRONIC IMMUNE RESPONSE DANGER INFLAMMATION CHRONIC COLLATERAL DAMAGE

CHRONIC CHRONIC IMMUNE RESPONSE DANGER INFLAMMATION CHRONIC COLLATERAL DAMAGE

CANCER

CHRONIC CHRONIC IMMUNE RESPONSE DANGER INFLAMMATION CHRONIC COLLATERAL DAMAGE

CANCER

CHRONIC CHRONIC IMMUNE RESPONSE DANGER INFLAMMATION CHRONIC COLLATERAL DAMAGE

CANCER

CHRONIC CHRONIC IMMUNE RESPONSE DANGER INFLAMMATION cancer: a “never‐healing wound” InflammationInflammation cancan PromotePromote Cancer:Cancer: collaborationcollaboration withwith KK‐‐rasras mutationmutation no smoking

4 cigarettes per day K‐ras mutation & normal myeloid cells

Takahashi et al. , Cancer Cell 2010

InflammationInflammation cancan PromotePromote Cancer:Cancer: collaborationcollaboration withwith KK‐‐rasras mutationmutation no smoking

4 cigarettes per day K‐ras mutation K‐ras mutation & + normal myeloid cells IKK‐/‐ myeloid cells

Takahashi et al. , Cancer Cell 2010

InflammationInflammation cancan PromotePromote Cancer:Cancer: collaborationcollaboration withwith KK‐‐rasras mutationmutation no smoking

4 cigarettes per day K‐ras mutation K‐ras mutation • ↓ NF‐B & + • ↓ pSTAT3 ‐/‐ normal myeloid cells IKK myeloid cells • ↓ IL‐6 • ↓ neutrophils • ↓ angiogenesis

Takahashi et al. , Cancer Cell 2010

InflammationInflammation cancan PromotePromote Cancer:Cancer: collaborationcollaboration withwith HPVHPV E6/E7E6/E7 oncogeneoncogene

TUMOR

tumor‐induced ANTIBODIES

De Visser et al., Cancer Cell 2005 Andreu et al., Cancer Cell 2010

InflammationInflammation cancan CauseCause MutationMutation

Able to repair DNA

days post acute gut inflammation

Meira et al., J. Clin. Invest. 2008

InflammationInflammation cancan CauseCause MutationMutation

Able to repair DNA

days post acute gut inflammation

Meira et al., J. Clin. Invest. 2008

InflammationInflammation cancan CauseCause MutationMutation

Meira et al., J. Clin. Invest. 2008

InflammationInflammation cancan CauseCause MutationMutation

deoxyguanosine 8‐hydroxydeoxyguanosine

Meira et al., J. Clin. Invest. 2008

TumorsTumors cancan induceinduce badbad inflammationinflammation TumorsTumors cancan induceinduce badbad inflammationinflammation

Spleen (no tumor)

Spleen (subcut. tumor)

Bronte et al., J. Immunol. 1999 TumorsTumors cancan induceinduce badbad inflammationinflammation

Normal Tumors induce immune system bad inflammation +  Blocks treatment T cell treatment

Marigo et al., Immunity 2010

TumorsTumors cancan induceinduce badbad inflammationinflammation

Normal Tumors induce immune system bad inflammation +  Blocks treatment T cell treatment

Cebpb‐deficient Tumors cannot induce immune system bad inflammation +  Treatment works T cell treatment

Marigo et al., Immunity 2010

TumorsTumors cancan induceinduce badbad inflammationinflammation

Ugel et al., Curr. Opin. Pharmacol. 2010

TumorsTumors cancan induceinduce badbad inflammationinflammation OncogenicOncogenic STAT3STAT3

Yu et al., Nat. Rev. Cancer 2009

TumorsTumors cancan induceinduce badbad inflammationinflammation OncogenicOncogenic STAT3STAT3

Yu et al., Nat. Rev. Cancer 2009

MutationsMutations cancan DriveDrive BadBad InflammationInflammation

Mutated BRAF  tumor cells produce

bad, imunosuppressive cytokines control BRAF control BRAF control BRAF shRNA shRNA shRNA shRNA shRNA shRNA

Sumimoto et al., J. Exp. Med.. 2006

MutationsMutations cancan DriveDrive BadBad InflammationInflammation

Mutated BRAF  tumor cells produce

bad, imunosuppressive cytokines control BRAF control BRAF control BRAF shRNA shRNA shRNA shRNA shRNA shRNA

block production of good cytokines in DCs

Sumimoto et al., J. Exp. Med.. 2006

Conclusion:Conclusion: InflammationInflammation andand CancerCancer

• Inflammation can Cause Cancer • Inflammation can Cause Mutation • Mutation can Cause Inflammation • Mutation can Cause Cancer • Cancer can Cause Inflammation InflammationInflammation andand Cancer:Cancer: AA ViciousVicious CycleCycle

MUTATION

CANCER

INFLAMMATION ClassicClassic HallmarksHallmarks ofof CancerCancer

Mantovani et al., Nature 2009 Hanahan & Weinberg, Cell 2000

InflammationInflammation isis (now)(now) aa ClassicClassic HallmarkHallmark ofof CancerCancer

Mantovani et al., Nature 2009 Hanahan & Weinberg, Cell 2000

InflammationInflammation isis (now)(now) aa ClassicClassic HallmarkHallmark ofof CancerCancer

Mantovani et al., Nature 2009 Hanahan & Weinberg, Cell 2000

InnateInnate ImmunityImmunity andand InflammationInflammation

• Definitions • Cells and Molecules • Innate Immunity and Inflammation in Cancer • Bad Inflammation • Good Inflammation • Therapeutic Implications GoodGood vs.vs. BadBad InflammationInflammation inin CancerCancer IFNIFN‐‐ SuppressesSuppresses HumanHuman TumorTumor DevelopmentDevelopment

Toyoda et al., J. Med. Genetics 2010 IFNIFN‐‐ SuppressesSuppresses HumanHuman TumorTumor DevelopmentDevelopment

At 17 years of age, the patient developed multifocal Squamous Cell Carcinomas on the face and both hands. Despite local tumour excision, multiple lesions occurred and the patient died at 20 years of age of disseminated SCC. Inherited disorders of IFN-mediated immunity may predispose patients to SCC.

Toyoda et al., J. Med. Genetics 2010 HumanHuman ImmuneImmune SystemSystem cancan SuppressSuppress ExistingExisting TumorsTumors forfor YearsYears

1982: patient with primary, resected melanoma 1997: declared disease‐free and “cured” 1998: died of brain hemorrhage, donated kidneys 2000: ‐ kidney recipient 1 died of metastatic donor melanoma ‐ kidney recipient 2 taken off immunosuppression; start IFN‐ ‐ kidney recipient 2 rejects kidney and melanoma

MacKie et al., NEJM 2003

HumanHuman ImmuneImmune SystemSystem cancan SuppressSuppress ExistingExisting TumorsTumors forfor YearsYears

MacKie et al., NEJM 2003

PostPost‐‐transplanttransplant ImmunosuppressionImmunosuppression IncreasesIncreases CancerCancer IncidenceIncidence

Vajdic & Van Leeuwen , Int. J. Cancer 2009 TypeType II IFNsIFNs SuppressSuppress GrowthGrowth ofof TransplantedTransplanted TumorsTumors

IFN‐ receptor blocking mAb

control mAb

Dunn et al. Nat. Immunol. 2005 TypeType II IFNsIFNs SuppressSuppress DevelopmentDevelopment ofof CarcinogenCarcinogen‐‐InducedInduced TumorsTumors

MCA carcinogen Dunn et al. Nat. Immunol. 2005 IFNIFN‐‐ treatmenttreatment enhancesenhances antianti‐‐ cancercancer vaccinationvaccination

Sikora et al. J. Immunol. 2009 IFNIFN‐‐ treatmenttreatment enhancesenhances antianti‐‐ cancercancer vaccinationvaccination

Sikora et al. J. Immunol. 2009 CpGCpG CausesCauses TumorTumor InflammationInflammation andand IntratumoralIntratumoral TT cellcell AccumulationAccumulation

Intratumoral PBS Intratumoral CpG Intravenous CpG

Lou et al. , unpublished results CpGCpG CausesCauses TumorTumor InflammationInflammation andand IntratumoralIntratumoral TT cellcell AccumulationAccumulation

i.t PBS i.t CpG vaccine + i.t PBS vaccine + i.t CpG

450 ) 2

(mm 300

size

P<0.01 150 Tumor

0 0 5 10 15 Days after Vaccination

Lou et al. , unpublished results Tumor‐ induced Inflammation

Dietary & Chronic Environment‐ Inflammation induced Cancer Autoimmunity Inflammation Infection

Adapted from Grivennikov et al. Cell 2010

BottomBottom Line:Line: InflammationInflammation cancan bebe GoodGood oror Bad:Bad: ProPro oror AntiAnti‐‐TumorTumor

Grivennikov et al. Cell 2010

InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat BlockBlock BadBad InflammationInflammation InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat BlockBlock BadBad InflammationInflammation • COX‐2 inhibitor Aspirin, Celecoxib (colorectal)

InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat BlockBlock BadBad InflammationInflammation • COX‐2 inhibitor Aspirin, Celecoxib (colorectal) • VEGF blocker Bevacizumab, Sorafenib (several) • IL‐1 blocker IL‐1Ra (MM) • Cytokine Regulators Lenalidomide (MDS, MM) • Kill Helicobacter Pylori Clarithrom./Amoxicillin (gastric) • Remove suppressors Cycl/Fludar + T cells (melanoma) • Cytotoxic Therapy? Radiation/Chemother. (all cancers) InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat BlockBlock BadBad InflammationInflammation • COX‐2 inhibitor Aspirin, Celecoxib (colorectal) • VEGF blocker Bevacizumab, Sorafenib (several) • IL‐1 blocker IL‐1Ra (MM) • Cytokine Regulators Lenalidomide (MDS, MM) • Kill Helicobacter Pylori Clarithrom./Amoxicillin (gastric) • Remove suppressors Cycl/Fludar + T cells (melanoma) • Cytotoxic Therapy? Radiation/Chemother. (all cancers) • Targeted Therapy? TKI inhibitors (many cancers)

InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat InduceInduce GoodGood InflammationInflammation InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat InduceInduce GoodGood InflammationInflammation • Bacteria BCG (bladder)

InIn thethe Clinic:Clinic: CancerCancer TherapiesTherapies thatthat InduceInduce GoodGood InflammationInflammation • Bacteria BCG (bladder) • TLR agonists Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) • Cytokines IL‐2 (melanoma, renal) IFN‐ (melanoma, renal, CML) • Antibodies aCTLA4 mAb (melanoma) • Surgery Danger/inflammation? (cervical)

Take Home Messages Take Home Messages Tumor‐ induced Inflammation

Dietary & Chronic Environment‐ Inflammation induced Cancer Autoimmunity Inflammation Infection

Therapy‐ • induced Inflammation is a classic hallmark of cancer Inflammation

• Innate Immunity & Inflammation can promote or suppress cancer

• Manipulating immunity can promote or suppress cancer

• Understanding of inflammatory cells & molecules in cancer is limited but growing, allowing therapeutic intervention