Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms & Their Application to Clinical Trials of Vaccines Part 1: The Basics Barbara K. Dunn NCI/Division of Cancer Prevention July 13, 2020
Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms Definition of IMMUNE SYSTEM -the bodily system that protects the body from foreign substances, cells, and tissues -by producing the immune response which includes the… (1) thymus, spleen, lymph nodes, special deposits of lymphoid tissue (as in the gastrointestinal tract and bone marrow), (2) macrophages, lymphocytes including the B cells and T cells, and (3) antibodies and cytokines
Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies: as drugs 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents II) Vaccines to prevent non-infection associated cancer (directed toward tumor associated antigens)
Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies: as drugs 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents II) Vaccines to prevent non-infection associated cancer (directed toward tumor associated antigens)
Context: Premalignant Progression to Cancer What is Carcinogenesis? Basement membrane/ boundary Normal Initiated Precancer/Premalignancy Cancer Mild Moderate Severe CIS Breast 14 - 18 yrs Atypical 6 - 10 yrs DCIS Breast Cancer Hyperplasia Cervix 9 - 13 yrs 10 - 20 yrs Cervical Cancer CIN I CIN III/CIS 5 - 20 yrs 5 - 15 yrs Colon Adenoma Colorectal Cancer ≥10 yrs 20 yrs 3 - 15 yrs Latent Clin. Prostate PIN Prostate Cancer Carc. Carc. Genetic changes cumulative
Context: Premalignant Progression to Cancer What is Carcinogenesis? Basement membrane/ boundary Normal Initiated Precancer/Premalignancy Cancer Mild Moderate Severe CIS Breast 14 - 18 yrs Atypical 6 - 10 yrs Cancer is a “genetic disease” DCIS Hyperplasia Cervix 9 - 13 yrs 10 - 20 yrs CIN I CIN III/CIS -not so simple! 5 - 20 yrs 5 - 15 yrs Colon Adenoma Microenvironment (includes the ≥10 yrs 20 yrs 3 - 15 yrs Latent Clin. Prostate PIN Carc. Carc. immune system ) Genetic changes cumulative See Mukherjee New Yorker article – “seed versus soil”
Context: Premalignant Progression to Cancer What is Carcinogenesis? Basement membrane/ boundary Normal Initiated Precancer/Premalignancy Cancer Mild Moderate Severe CIS Breast 14 - 18 yrs Atypical 6 - 10 yrs Cancer is a “genetic disease” DCIS Hyperplasia ● Drugs Cervix 9 - 13 yrs 10 - 20 yrs CIN I CIN III/CIS preventive intervention -not so simple! ● Immune 5 - 20 yrs 5 - 15 yrs Colon Adenoma therapies Microenvironment ( immune system ) ≥10 yrs 20 yrs 3 - 15 yrs Latent Clin. Prostate PIN Carc. Carc. Genetic changes cumulative See Mukherjee New Yorker article – “seed versus soil”
immunoediting CANCER GROWTH Elimination Equilibrium Escape IMMUNE RESPONSE Adapted from Zitvogel, Nature Reviews 6 October 2006 Figure 1
In cancer: T H =“good”cells T reg =“bad”cells Lollini, Nature Reviews Cancer 6 As carcinogenesis progresses-> March 2006 immune system gets suppressed = immunoediting : “Good” immune cells go away & “bad” cells emerge & dominate
Physical components of the immune system: Hematopoiesis Cells of the immune system: macrophages, lymphocytes (B cells, T cells), etc. Molecules of the immune system: Antibodies, cytokines, etc. http://www.google.com/search?q=hemato poiesis&tbm=isch&tbo=u&source=univ&s a=X&ei=NxD0Uaf7LtL54AP264CgBQ&sqi =2&ved=0CDQQsAQ&biw=1093&bih=47
Physical components of the immune system: Hematopoiesis B Two main lineages T Cells of the immune system: macrophages, lymphocytes (B cells, T cells), etc. Molecules of the immune system: Antibodies, cytokines, etc. Antibodies http://www.google.com/search?q=hematopoie sis&tbm=isch&tbo=u&source=univ&sa=X&ei= Humeral Cellular immunity NxD0Uaf7LtL54AP264CgBQ&sqi=2&ved=0C immunity DQQsAQ&biw=1093&bih=470
Basic Immunological Mechanisms: Innate versus Adaptive Immunity I. Basic immunologic mechanisms hierarchy of the immune system II. Application to prevention & treatment of cancer 1. Antibodies: as drugs a. Innate versus Adaptive Immunity – 2. Vaccines: general principles & your vaccine 2 compartments trials & more… b. Focus on Adaptive Immunity – 2 cell types: I) Vaccines to prevent cancers caused by B cells and T cells infectious agents (1) B cells = humoral immunity (antibodies) II) Vaccines to prevent non-infection (2) T cells = cellular immunity (cells do the work) (a) Cytolytic T cells/CTLs (CD8) associated cancer (directed (b) T helper cells (CD4) toward tumor associated antigens) 1- Type 1 response 2- Type 2 response
Basic Immunological Mechanisms: Innate versus Adaptive Immunity 2 Compartments of Immunity Innate Adaptive versus No specific molecule/antigen Specific molecule/antigen needed to induce innate needed to induce adaptive response response Nonspecific immune response Quick response to Response takes time/ slow generalized “inducer” (0-4 hours) (>96 hours) Short-lived response Lasts long time (lifelong) - memory Macrophages, dendritic cells, T cells, B cells, dendritic natural killer cells, neutrophils cells
■ Innate immunity: CELLS OF THE INNATE IMMUNE SYSTEM Neutrophil Antigen Presenting Cell skin (Adaptive Dendritic immunity) Cell Myeloid lineage Macrophage Natural Killer http://missinglink.ucsf.edu/lm/immunology_module/prologue/ objectives/obj02.html
■ Adaptive immunity: Hematopoiesis B T Focus: Adaptive Immunity Antibodies http://www.google.com/search?q=hematopoie sis&tbm=isch&tbo=u&source=univ&sa=X&ei= NxD0Uaf7LtL54AP264CgBQ&sqi=2&ved=0C DQQsAQ&biw=1093&bih=470
■ Adaptive Immunity ■ Humoral versus Cellular immunity B cells T cells T-cell receptors antibodies The cell does the work Humoral immunity in cancer: important in IgE fighting viruses (including those causing cancer) IgA IgG e.g. HPV vaccines, Covid-19 vaccines IgD IgM
■ Adaptive Immunity: B cells ■ Humoral versus Cellular immunity B cells T cells T-cell receptors IgE IgA IgG IgD antibodies The cell does IgM the work Immunoglobulin (Ig) Humoral immunity in cancer: important in IgE fighting viruses (including those causing cancer) IgA IgG e.g. HPV vaccines, Covid-19 vaccines IgD IgM
■ Adaptive Immunity: T cells = cellular immunity (cells do the work) T CD8 CD4 CD4 subtypes CD4 CD8 CD=cluster of differentiation
Adaptive Immunity: T cells = T cells = cellular immunity (cells do the work) cellular immunity (cells do the work) In cancer: We want T H 1 cells - to kill cancer cells We do not want Treg & T H 2 cells CD4 subtypes Yes! No
Adaptive Immunity: T cells = cellular immunity (cells do the work) In cancer : We want T H 1 cells - to kill cancer cells We do not want Treg & T H 2 cells In normal cells: We want Treg cells-to protect these normal cells CD4 subtypes Distinguish Self from Non-self: save the self! Immune Tolerance No Yes
■ Adaptive Immunity:Cellular Immunity (T cells) Antigen Presentation & T Cell Activation Specific part of T cell activation Infection (virus) Cancer Bad Antigen TCR Processed MHC/ T cell Bad HLA Antigen (epitope) APC / Signal 1 specific antigen presenting cell IFN- γ IL-17 MHC = Major Histocompatibility Antigen T cell activation TCR = T cell receptor HLA = Human Leukocyte Antigen
■ Adaptive Immunity:Cellular Immunity (T cells) Antigen Presentation & T Cell Activation Generalized part of T cell activation Infection (virus) Signal 2 Cancer Nonspecific Bad Antigen (CD80,86) B7 CD28 TCR Processed MHC/ T cell Bad HLA Antigen (epitope) APC / Signal 1 specific antigen presenting cell IFN- γ IL-17 MHC = Major Histocompatibility Antigen T cell activation TCR = T cell receptor HLA = Human Leukocyte Antigen
■ Adaptive Immunity: Cellular Immunity Antigen Presentation & T Cell Activation Antagonizing T cell activation Infection (virus) Cancer Bad Antigen (CD80,86) B7 CD28 TCR Processed MHC/ T cell Bad HLA CTLA-4 Antigen (epitope) or PD-1 APC / B7 or PD-L1 antigen presenting cell (CD80,86) immunoediting T cell inactivation = immune suppression CTLA-4 = cytotoxic T-lymphocyte-associated protein PD-1 = programmed cell death protein-1
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