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Innate immune response to breast cancer
- 1. Innate Immune Response To Breast Cancer PRESENTED BY: ALEENA HAQQI (MS-HCB 2019) COURSE : ADVANCES IN IMMUNOLOGY
- 2. Introduction To Breast Cancer Every 1 in 8 women It effects about 12% women worldwide Signs of breast cancer • A lump in the breast • A change in shape • Dimpling of the skin Cancer that develops from breast tissue
- 3. TYPES OF BREAST CANCER Cancers developing from the ducts are known as ductal carcinomas, while those developing from lobules are known as lobular carcinomas non-invasive breast cancer (carcinoma in situ) – found in the ducts of the breast (ductal carcinoma in situ, or DCIS) which has not spread into the breast tissue surrounding the ducts. invasive breast cancer – where the cancer cells have spread through the lining of the ducts into the surrounding breast tissue. This is the most common type of breast cancer. Lobule Duct cells Duct Lobular cells
- 4. Causes of Breast Cancer GENETIC BASIS BRCA1 mutation or BRCA2 mutation ATM, BARD1, BRIP1, CDH1, CHEK2 ENVIROMENTAL FACTORS OBIESITY RADIATION EXPOSURE FAMILY HISTORY
- 5. Interaction Between The Immune System And Cancer Cells Three Phases Of Interaction : Elimination;Equilibrium; And Escape, Which Are Referred To As The “Three Es” Of Cancer Immunoediting. CD47, function as “don’t-eat-me” signals and can prevent the attack of normal cells by macrophages, Tumor cells may also use this mechanism to evade immune attacks
- 6. Innate Immune Response As Suppressor of Breast Cancer ActivationofMonocytesandMacrophages Bacterial Components Thrombospondin MUCIN-1 IL-12 & IFN (gamma) Activation of Macrophages results in Tumorcidal activities IL-2, IL-12 & TNFα causes The activation of tumorcidal activities in Neutrophills, Granulocytes and NK cells
- 8. Innate Immune Response TO BC TGF β Il-4 Il-3 Type II Response M2 Polarization Tissue Remodeling Angiogenesis Anti- inflammatory cytokines Support tumor growth Immune suppression
- 9. Breast Cancer Immune Enviroment Tumor & Stromal Cells IL-10 & TGFβ Impair immune cells to secrete Pro-inflammatory cytokines Incresead Treg More anti- inflammatory signals Perforin & Granzymes Kills innate immune cells
- 10. BC Immune Enviroment at a Glance Solid Tumor More fibrillar collagen Macrophage culture on it Impaired cytotoxicity Immune cell Collagen receptor (LAIRs) Inhibit Nk cell cytotoxic activity Immune suppression Tumors Spontaneous cell death Phagocytes take up apoptotic cells Inhibit immune response
- 11. Innate Immune Response as Breast Cancer Promoter Screte Matrix Metallo Proteinases (MMPs) Degrade ECM Molecules Enhance Tumor Invasion and Metastasis Secrete Epidermal Growth Factor (EGF) Protrusions and invasive Phenotype in BC Secrete TGF β & IL-10 Secrete Chemokine (CCL2) Immune suppressive enviroment of tumor Recruitment of monocytes Secrete VEGF Extravasation of tumor cells Express Programmaed Cell Death Receptor (PDL-1) T - Cell Death Hypoxic Tumor Enviroment – Accumulation Of (Tumor Associated Macrophages) TAMs
- 12. Other Immune cells as BC Promoter DENDRITIC CELLS Deplete Arginine in tumor microenviroment T cell Apoptosis Prevent adaptive anti tumor Response MDSC • Sequester Cysteine • Impair T cell activation • Impeding T cell Response • Inhibit DC maturation & NK cell activity • Inhibit immune response COMMON FUNCTION • Secretion of Anti- Inflammatory Factors • Potentiate Tumor Promoting Effects
- 14. Crosstalk between Innate & Adaptive Immune System By engulfing dead tumor cells and presenting antigens to T cells, macrophages and dcs “visualize” the tumor for the adaptive immune system. Tumor specific antigens (tsa), which are mutated or aberrantly glycosylated proteins that are unique to tumor cells Provide well-suited targets for adaptive immunity and are found in high amounts in human breast cancer samples While dcs are considered to be the main antigen presenting cells, macrophages also play a role in antigen presentation and in the activation of an adaptive immune response to tumors
Editor's Notes
- Women who have a BRCA1 mutation or BRCA2 mutation (or both) can have up to a 72% risk of being diagnosed with breast cancer during their lifetimes
- the ‘elimination’ phase, the immune system may succeed in destroying all tumor cells. If that does not happen, it may still be able to control tumor growth but not completely eradicate it. This phase is referred to as the ‘equilibrium’ phase. Finally, due to selection pressure from the immune system, some cancer cells develop enough resistance that they can escape the immune system, leading to a failure of immune-mediated cancer control [31]. This is referred to as the ‘escape’ phase. Cancers develop resistance by expressing reduced levels of MHC 1 and costimulatory molecules. They can produce factors that suppress the immune system, which enables them to avoid recognition by the immune system
- Tumor-suppressing activities of innate immune cells in breast cancer. Anti-tumor activities of innate immune cells can be induced by type I polarizing, pro-inflammatory stimuli, including lipopolysaccharides (LPS) and interferon (IFN)-γ and likely also by endogenous ligands of toll-like receptors (TLRs) including high mobility group box protein 1 (HMGB-1) and heat shock proteins (HSPs). Tumor-suppressing macrophages and dendritic cells (DCs) kill tumor cells or suppress their proliferation via the release of tumor necrosis factor (TNF)-α, type I interferons (IFNs), reactive oxygen species (ROS) and nitric oxide (NO) as well as interleukins (ILs), like IL-1β or IL-12. IL-12 has several effects, including the inhibition of angiogenesis and the activation of natural killer (NK) cells, type I T helper (Th1) and cytotoxic T cells. Th1 cells secrete IFN-γ, creating a feedback loop by enhancing pro-inflammatory activities of innate immune cells. Pro-inflammatory cytokines also activate anti-tumor activities in neutrophil granulocytes, which in turn secrete TNF-α, IL- 12, IFNs and reactive oxygen species (ROS)