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