Innate Immunity and Inflammation
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1 SITC Primer on Tumor Immunology and Biological Therapy of Cancer Innate Immunity and Inflammation Willem Overwijk, Ph.D. MD Anderson Cancer Center Center for Cancer Immunology Research Houston, TX
2 Innate Immunity and Inflammation Definitions Cells and Molecules Innate Immunity and Inflammation in Cancer Bad Inflammation Good Inflammation Therapeutic Implications
3 Innate Immunity and Inflammation Definitions Cells and Molecules Innate Immunity and Inflammation in Cancer Bad Inflammation Good Inflammation Therapeutic Implications
4 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
5 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
6 Innate Immunity and Inflammation are vague terms Specific cell types and molecules orchestrate specific types of inflammation
7 Innate Immunity and Inflammation are vague terms Specific cell types and molecules orchestrate specific types of inflammation Innate Immunity A Innate Immunity B Inflammation A Inflammation B
8 Innate Immunity and Inflammation can mean many things Specific cell types and molecules orchestrate specific types of inflammation Innate Immunity A Innate Immunity B Inflammation A Inflammation B Some immune responses promote cancer, others suppress it
9 Innate Immunity and Inflammation Functions: Rapid response to tissue damage Limit spread of infection Initiate adaptive immune response (T, B) Initiate tissue repair
10 Innate Immunity and Inflammation: A Paper Cut Janeway, Immunobiology, 7 th Ed.
11 Innate Immunity and Inflammation: A Paper Cut Janeway, Immunobiology, 7 th Ed.
12 Innate Immunity and Inflammation: A Paper Cut Janeway, Immunobiology, 7 th Ed.
13 Innate Immunity and Inflammation: A Paper Cut Janeway, Immunobiology, 7 th Ed.
14 Innate Immunity and Inflammation Definitions Cells and Molecules Innate Immunity and Inflammation in Cancer Bad Inflammation Good Inflammation Therapeutic Implications
15 Innate Immune Molecules: Cyclooxygenase 2 2 (COX 2) Recognize inflammation Cause inflammation
16 Innate Immune Molecules: Complement System Recognize pathogens antibodies lectins Cause pathogen clearance chemotaxis inflammation Janeway, Immunobiology, 7 th Ed.
17 Innate Immune Molecules: type I IFN( ) Induced by infection/damage Antiviral/Antiproliferative Increase innate and adaptive immunity Cause inflammation
18 Innate Immune Cells Janeway, Immunobiology, 7 th Ed.
19 Innate Immune Cells Janeway, Immunobiology, 7 th Ed.
20 Innate Immune Cells Janeway, Immunobiology, 7 th Ed.
21 Innate Immune Cells: granulocytes ( ) Antigen Presentation Recognize pathogens antibodies Cause pathogen clearance inflammation Janeway, Immunobiology, 7 th Ed.
22 Innate Immune Cells: phagocytes Monocyte Blood precursor of tissue Macrophages and Dendritic Cells Recognize pathogens antibodies Cause pathogen clearance adaptive immunity inflammation Janeway, Immunobiology, 7 th Ed.
23 Recognize pathogens stressed cells altered self Cause Innate Immune Cells: NK, NKT and T cells pathogen clearance stressed/abnormal cell clearance inflammation
24 Danger signals start inflammation PATHOGENS DAMAGE Rubartelli & Lotze, Trends in Immunology 2007
25 Danger signals start inflammation PATHOGENS DAMAGE Rubartelli & Lotze, Trends in Immunology 2007
26 Receptors sense Danger: Pathogens Kawai & Akira, Nat. Immunol. 2010
27 Receptors sense Danger: Damage Kawai & Akira, Nat. Immunol. 2010
28 Innate Immunity and Inflammation Definitions Cells and Molecules Innate Immunity and Inflammation in Cancer Bad Inflammation Good Inflammation Therapeutic Implications
29 Innate Immunity and Inflammation in Cancer Outcomes vary: Promote cancer (Bad inflammation) Suppress cancer (Good inflammation)
30 Innate Immunity and Inflammation Definitions Cells and Molecules Innate Immunity and Inflammation in Cancer Bad Inflammation Good Inflammation Therapeutic Implications
31 Bad Inflammation Causes Cancer DANGER cellular damage caused by pathogens physical damage chemicals UV etc
32 DANGER IMMUNE RESPONSE INFLAMMATION
33 DANGER IMMUNE RESPONSE INFLAMMATION
34 COLLATERAL DAMAGE DANGER IMMUNE RESPONSE INFLAMMATION
35 COLLATERAL DAMAGE IMMUNE RESPONSE INFLAMMATION
36 COLLATERAL DAMAGE DANGER IMMUNE RESPONSE INFLAMMATION
37 COLLATERAL DAMAGE CHRONIC DANGER IMMUNE RESPONSE INFLAMMATION
38 CHRONIC COLLATERAL DAMAGE CHRONIC DANGER CHRONIC IMMUNE RESPONSE INFLAMMATION
39 CHRONIC COLLATERAL DAMAGE CANCER CHRONIC DANGER CHRONIC IMMUNE RESPONSE INFLAMMATION
40 CHRONIC COLLATERAL DAMAGE CANCER CHRONIC DANGER CHRONIC IMMUNE RESPONSE INFLAMMATION
41 CHRONIC COLLATERAL DAMAGE CANCER CHRONIC DANGER CHRONIC IMMUNE RESPONSE INFLAMMATION cancer: a never healing wound
42 Inflammation can Promote Cancer: collaboration with K ras K mutation no smoking 4 cigarettes per day K ras mutation & normal myeloid cells Takahashi et al., Cancer Cell 2010
43 Inflammation can Promote Cancer: collaboration with K ras K mutation no smoking 4 cigarettes per day K ras mutation & normal myeloid cells K ras mutation + IKK / myeloid cells Takahashi et al., Cancer Cell 2010
44 Inflammation can Promote Cancer: collaboration with K ras K mutation no smoking 4 cigarettes per day K ras mutation & normal myeloid cells K ras mutation + IKK / myeloid cells pstat3 IL 6 neutrophils angiogenesis myeloid cells NF B Takahashi et al., Cancer Cell 2010
45 Inflammation can Promote Cancer: collaboration with HPV E6/E7 oncogene TUMOR tumor induced ANTIBODIES De Visser et al., Cancer Cell 2005 Andreu et al., Cancer Cell 2010
46 Tumors can induce bad inflammation
47 Tumors can induce bad inflammation Spleen (no tumor) Spleen (subcut. tumor) Bronte et al., J. Immunol. 1999
48 Tumors can induce bad inflammation Ugel et al., Curr. Opin. Pharmacol. 2010
49 Tumors can induce bad inflammation Oncogenic STAT3 Yu et al., Nat. Rev. Cancer 2009
50 Tumors can induce bad inflammation Oncogenic STAT3 Yu et al., Nat. Rev. Cancer 2009
51 Mutations can Drive Bad Inflammation Mutated BRAF tumor cells produce bad, imunosuppressive i cytokines control shrna BRAF shrna control shrna BRAF shrna control shrna BRAF shrna Sumimoto et al., J. Exp. Med. 2006
52 Mutations can Drive Bad Inflammation Mutated BRAF tumor cells produce bad, imunosuppressive i cytokines control shrna BRAF shrna control shrna BRAF shrna control shrna BRAF shrna block production of good cytokines in DCs Sumimoto et al., J. Exp. Med. 2006
53 Mutations can Drive Bad Inflammation Mutated BRAF tumor cells produce bad, imunosuppressive i cytokines promote expression of immunosuppressive molecules Khalili et al., Clin. Cancer Res. 2012
54 Conclusion: Inflammation and Cancer Inflammation can Cause Cancer Inflammation can Cause Mutation Mutation can Cause Inflammation Mutation can Cause Cancer Cancer can Cause Inflammation
55 Inflammation and Cancer: A Vicious Cycle CANCER MUTATION INFLAMMATION
56 Classic Hallmarks of Cancer Mantovani et al., Nature 2009 Hanahan & Weinberg, Cell 2000
57 Inflammation is (now) a Classic Hallmark of Cancer Mantovani et al., Nature 2009 Hanahan & Weinberg, Cell 2000
58 Inflammation is (now) a Classic Hallmark of Cancer Mantovani et al., Nature 2009 Hanahan & Weinberg, Cell 2000
59 Innate Immunity and Inflammation Definitions Cells and Molecules Innate Immunity and Inflammation in Cancer Bad Inflammation Good Inflammation Therapeutic Implications
60 Good vs. Bad Inflammation in Cancer
61 IFN Suppresses Human Tumor Development Toyoda et al., J. Med. Genetics 2010
62 IFN Suppresses Human Tumor Development 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
63 Human Immune System can Suppress Existing Tumors for Years 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
64 Human Immune System can Suppress Existing Tumors for Years 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
65 Post transplant transplant Immunosuppression Increases Cancer Incidence Vajdic & Van Leeuwen, Int. J. Cancer 2009
66 Type I IFNs Suppress Growth of Transplanted Tumors IFN receptor blocking mab control mab Dunn et al. Nat. Immunol. 2005
67 IFN treatment enhances anti cancer vaccination Sikora et al. J. Immunol. 2009
68 IFN treatment enhances anti cancer vaccination Sikora et al. J. Immunol. 2009
69 CpG Causes Tumor Inflammation and Intratumoral T cell Accumulation Intratumoral PBS Intratumoral CpG Intravenous CpG Lou et al., J. Immunother. 2011
70 CpG Causes Tumor Inflammation and Intratumoral T cell Accumulation 450 i.t PBS i.t CpG vaccine + i.t PBS vaccine + i.t CpG Tumor size (mm 2 ) P< Days after Vaccination Lou et al., J. Immunother. 2011
71 Tumorinduced Inflammation Dietary & Environmentinduced Inflammation Cancer Chronic Inflammation Autoimmunity Infection Adapted from Grivennikov et al. Cell 2010
72 Bottom Line: Inflammation can be Good or Bad: Pro or Anti Tumor Grivennikov et al. Cell 2010
73 In the Clinic: Cancer Therapies that Block Bad Inflammation
74 In the Clinic: Cancer Therapies that Block Bad Inflammation COX 2 inhibitor Aspirin, Celecoxib (colorectal)
75 In the Clinic: Cancer Therapies that Block Bad Inflammation COX 2 inhibitor VEGF blocker Aspirin, Celecoxib (colorectal) Bevacizumab, Sorafenib (several)
76 In the Clinic: Cancer Therapies that Block Bad Inflammation COX 2 inhibitor VEGF blocker IL 1 blocker Aspirin, Celecoxib (colorectal) Bevacizumab, Sorafenib (several) IL 1Ra (MM)
77 In the Clinic: Cancer Therapies that Block Bad Inflammation COX 2 inhibitor VEGF blocker IL 1 blocker Cytokine Regulators Aspirin, Celecoxib (colorectal) Bevacizumab, Sorafenib (several) IL 1Ra (MM) Lenalidomide (MDS, MM)
78 In the Clinic: Cancer Therapies that Block Bad Inflammation 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)
79 In the Clinic: Cancer Therapies that Block Bad Inflammation 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)
80 In the Clinic: Cancer Therapies that Block Bad Inflammation 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)
81 In the Clinic: Cancer Therapies that Block Bad Inflammation 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)
82 In the Clinic: Cancer Therapies that Induce Good Inflammation
83 In the Clinic: Cancer Therapies that Induce Good Inflammation Bacteria BCG (bladder)
84 In the Clinic: Cancer Therapies that Induce Good Inflammation Bacteria TLR agonists BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma)
85 In the Clinic: Cancer Therapies that Induce Good Inflammation Bacteria TLR agonists Cytokines BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) IL 2 (melanoma, renal) IFN (melanoma, renal, CML)
86 In the Clinic: Cancer Therapies that Induce Good Inflammation Bacteria TLR agonists Cytokines Antibodies BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) IL 2 (melanoma, renal) IFN (melanoma, renal, CML) actla4/apd(l) 1 mab (melanoma)
87 In the Clinic: Cancer Therapies that Induce Good Inflammation Bacteria TLR agonists Cytokines Antibodies Surgery BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) IL 2 (melanoma, renal) IFN (melanoma, renal, CML) actla4/apd(l) 1 mab (melanoma) Danger/inflammation? (cervical)
88 In the Clinic: Cancer Therapies that Bacteria TLR agonists Induce Good Inflammation BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) Cytokines IL 2 (melanoma, renal) IFN (melanoma, renal, CML) Antibodies actla4/apd(l) 1 mab (melanoma) Surgery Danger/inflammation? (cervical) Hem. Stem Cells Stem Cell Transpl. (leukemia, lymphoma)
89 In the Clinic: Cancer Therapies that Bacteria TLR agonists Induce Good Inflammation BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) Cytokines IL 2 (melanoma, renal) IFN (melanoma, renal, CML) Antibodies actla4/apd(l) 1 mab (melanoma) Surgery Danger/inflammation? (cervical) Hem. Stem Cells Stem Cell Transpl. (leukemia, lymphoma) T cells Adoptive T cell Transfer (melanoma)
90 In the Clinic: Cancer Therapies that Bacteria TLR agonists Induce Good Inflammation BCG (bladder) Imiquimod (basal cell carcinoma) CpG (B cell lymphoma) Cytokines IL 2 (melanoma, renal) IFN (melanoma, renal, CML) Antibodies actla4/apd(l) 1 mab (melanoma) Surgery Danger/inflammation? (cervical) Hem. Stem Cells Stem Cell Transpl. (leukemia, lymphoma) T cells Adoptive T cell Transfer (melanoma) Vaccine PAP loaded DCs (prostate)
91 Take Home Messages Tumorinduced Inflammation Dietary & Environmentinduced Inflammation Cancer Chronic Inflammation Autoimmunity Infection Inflammation is a classic hallmark of cancer Therapyinduced 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
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