Immune disordes: cancer, Prof. Mohamed Labib Salem
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محاضرة للأستاذ الدكتور محمد لبيب سالم لطلاب الفرقة الرابعة كلية العلوم تخصص علم الحيوان وكيمياء - جامعة طنطا
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Immune disordes: cancer, Prof. Mohamed Labib Salem
- 1. ImmuneImmune DisordersDisorders Dr. Mohamed Labib Salem Prof. of Immunology Faculty of Science Tanta University
- 4. Immune DisordersImmune Disorders 1. Hypo immunity Cancer Chemotherapy 1. Hyper immunity Autoimmunity Hypersensitivity (types I, II, III, IV) 1. Failure of immunity Infection (Bacteria-Viruses-Fungus – parasites - protozoa)
- 5. Cancer
- 6. What Causes Cancer? Some viruses or bacteria Heredity Diet Hormones RadiationSome chemicals Causes of Immune disorders
- 7. Genes and Cancer Chromosomes are DNA molecules Heredity RadiationChemicals Viruses Causes of Immune disorders
- 8. DNA Mutation Additions Deletions Normal gene Single base change DNA C T A G C G A A C TAC A G G C G C T AAC A C T A G C T A A C TAC A G A A C TAC Causes of Immune disorders
- 9. Loss of Normal Growth Control Cancer cell division Fourth or later mutation Third mutation Second mutation First mutation Uncontrolled growth Cell Suicide or Apoptosis Cell damage— no repair Normal cell division
- 10. Different Kinds of Cancer Lung Breast (women) Colon Bladder Prostate (men) Some common sarcomas: Fat Bone Muscle Lymphomas: Lymph nodes Leukemias: Bloodstream Some common carcinomas:
- 11. Naming Cancers Prefix Meaning adeno- gland chondro- cartilage erythro- red blood cell hemangio- blood vessels hepato- liver lipo- fat lympho- lymphocyte melano- pigment cell myelo- bone marrow myo- muscle osteo- bone Cancer Prefixes Point to Location
- 12. Malignant versus Benign Tumors Malignant (cancer) cells invade neighboring tissues, enter blood vessels, and metastasize to different sites Time Benign (not cancer) tumor cells grow only locally and cannot spread by invasion or metastasis
- 13. Invasion and Metastasis 3 Cancer cells reinvade and grow at new location 1 Cancer cells invade surrounding tissues and blood vessels 2 Cancer cells are transported by the circulatory system to distant sites
- 15. Cancer Tends to Involve Multiple Mutations Malignant cells invade neighboring tissues, enter blood vessels, and metastasize to different sites More mutations, more genetic instability, metastatic disease Proto-oncogenes mutate to oncogenes Mutations inactivate DNA repair genes Cells proliferate Mutation inactivates suppressor gene Benign tumor cells grow only locally and cannot spread by invasion or metastasis Time
- 16. Cancer Tends to Corrupt Surrounding Environment Growth factors = proliferation Blood vessel Proteases Cytokines Matrix Fibroblasts, adipocytes Invasive Cytokines, proteases = migration & invasion
- 17. Immune surveillance/editing of tumors
- 19. Effectors that can kill Cancer Antibody Helper T cell Natura l killer cell Macrophage Cytotoxic T cell Cancer cells Prof. Mohamed Labib Salem
- 20. ? ? ? ? ? Typical Events Essential for Anti-tumor Immunity Prof. Mohamed Labib Salem
- 21. The smart interaction Immune cells Cancer Cells Cancer cellsHost Tumor microenvironment
- 22. Why does cancerWhy does cancer therapy fail?therapy fail? Prof. Mohamed Labib Salem
- 24. Melanoma growthMelanoma growth in micein mice
- 26. • Tumor cells originate from self (not foreign) • Tumor favor expansion of Regulatory cells that inhibit tumor-specific T-cell activities • Downregulation of Ag expression in tumor cells. • Secretion of immunosuppressive factors. • Death-receptors such as CD95 and TRAIL receptor are mutated or lost entirely. • Secretion of factors that favor emergence of suppressor immune cells such as Treg cells and myeloid derived suppressorcells Causes of Failure of Cancer Immunotherapy Intrinsic mechanisms
- 27. Causes of Failure of Cancer Immunotherapy Intrinsic/extrinsic mechanisms
- 28. Causes of Failure of Cancer Immunotherapy Extrinsic mechanisms • Tumor-specific T cells are absent. • Tumor-reactive immune cells do not localize to the tumor. • T cells fail to proliferate and persist in response to tumors. • Emergence and sustainability of suppressor immune cells such as Treg cells and myeloid derived suppressorcells Prof. Mohamed Labib Salem
- 29. Clinically Un-detectable Localized Disease Advanced Disease 1:10,000 T cells 1:50 T cells 1:2 T cells DiseaseBurden Causes of Failure of Cancer Immunotherapy High tumor cells/T cell ratio Prof. Mohamed Labib Salem
- 30. 0 2 4 6 8 1 3 5 7 10 14 21 30 60 120 CD8+Tcellresponse Days Post Vaccination Rapid expansion Rapid contraction Low memory 10 12 Tumor antigen alone Tumor antigen + Danger signal Causes of Failure of Cancer Immunotherapy Rapid contraction of T cells upon vaccination Prof. Mohamed Labib Salem
- 33. Regulatory immune cells Immunity is controlled by the balance between stimulatory/regulatory cells Treg MDSC NKT cells B cells pDCs Stimulatory immune cells Dendritic cells CD4+ T cells CD8+ T cells NK cells Prof. Mohamed Labib Salem
- 34. Tumor-induced Immune Dysfunction MDSC IL-10 Arginase ROS, RNS IDO: depletes L- tryptophan, results in T cell unresponsiveness Inhibitory/ death R:s Inhibitory/ death receptors: FasL TGF-β PGE2 ROS, RNS: reactive oxygen species results in T cell un- responsiveness TGF- and or IL-10 fromβ Treg, MDSC, and tumor cells suppress T cells Treg IDO MDSC/ DC Arginase: depletes L- arginine, results in T cell unresponsiveness Prof. Mohamed Labib Salem
- 35. Suppression of anti-tumor immunity by myeloid-derived suppressor cells (MDSC)
Editor's Notes
- Cancer is often perceived as a disease that strikes for no apparent reason. While scientists don’t yet know all the reasons, many of the causes of cancer have already been identified. Besides intrinsic factors such as heredity, diet, and hormones, scientific studies point to key extrinsic factors that contribute to the cancer’s development: chemicals (e.g., smoking), radiation, and viruses or bacteria.
- Chemicals (e.g., from smoking), radiation, viruses, and heredity all contribute to the development of cancer by triggering changes in a cell’s genes. Chemicals and radiation act by damaging genes, viruses introduce their own genes into cells, and heredity passes on alterations in genes that make a person more susceptible to cancer. Genes are inherited instructions that reside within a person’s chromosomes. Each gene instructs a cell how to build a specific product--in most cases, a particular kind of protein. Genes are altered, or “mutated,” in various ways as part of the mechanism by which cancer arises.
- Genes can be mutated in several different ways. The simplest type of mutation involves a change in a single base along the base sequence of a particular gene--much like a typographical error in a word that has been misspelled. In other cases, one or more bases may be added or deleted. And sometimes, large segments of a DNA molecule are accidentally repeated, deleted, or moved.
- Cancer arises from a loss of normal growth control. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted. This disruption can result from uncontrolled cell growth or loss of a cell’s ability to undergo cell suicide by a process called“apoptosis.” Apoptosis, or “cell suicide,” is the mechanism by which old or damaged cells normally self-destruct.
- Cancer can originate almost anywhere in the body. Carcinomas, the most common types of cancer, arise from the cells that cover external and internal body surfaces. Lung, breast, and colon are the most frequent cancers of this type in the United States. Sarcomas are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscle. Lymphomas are cancers that arise in the lymph nodes and tissues of the body’s immune system. Leukemias are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream.
- Scientists use a variety of technical names to distinguish the many different types of carcinomas, sarcomas, lymphomas, and leukemias. In general, these names are created by using different Latin prefixes that stand for the location where the cancer began its unchecked growth. For example, the prefix “osteo” means bone, so a cancer arising in bone is called an osteosarcoma. Similarly, the prefix “adeno” means gland, so a cancer of gland cells is called adenocarcinoma--for example, a breast adenocarcinoma.
- Depending on whether or not they can spread by invasion and metastasis, tumors are classified as being either benign or malignant. Benign tumors are tumors that cannot spread by invasion or metastasis; hence, they only grow locally. Malignant tumors are tumors that are capable of spreading by invasion and metastasis. By definition, the term “cancer” applies only to malignant tumors.
- Cancers are capable of spreading throughout the body by two mechanisms: invasion and metastasis. Invasion refers to the direct migration and penetration by cancer cells into neighboring tissues. Metastasis refers to the ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream, and then invade normal tissues elsewhere in the body.
- Cancer may begin because of the accumulation of mutations involving oncogenes, tumor suppressor genes, and DNA repair genes. For example, colon cancer can begin with a defect in a tumor suppressor gene that allows excessive cell proliferation. The proliferating cells then tend to acquire additional mutations involving DNA repair genes, other tumor suppressor genes, and many other growth-related genes. Over time, the accumulated damage can yield a highly malignant, metastatic tumor. In other words, creating a cancer cell requires that the brakes on cell growth (tumor suppressor genes) be released at the same time that the accelerators for cell growth (oncogenes) are being activated.
- In addition to all the molecular changes that occur within a cancer cell, the environment around the tumor changes dramatically as well. The cancer cell loses receptors that would normally respond to neighboring cells that call for growth to stop. Instead, tumors amplify their own supply of growth signals. They also flood their neighbors with other signals called cytokines and enzymes called proteases. This action destroys both the basement membrane and surrounding matrix, which lies between the tumor and its path to metastasis--a blood vessel or duct of the lymphatic system.