Cancer Immunology, molecular mechanisms.pptx

cancer immunology

1. Cancer Immunology Molecular basis of the cancer Host and tumor interface immune evasion in the cancer cytokines in the cancer therapy. BY: QALI HASSAN MOHAMMED QALI

2. Introduction Cancer   immunology   studies interactions between cancer cells and the immune system. The development and treatment of cancer is affected by  immune system function . Certain cancers can contribute to suppression or abnormal function of the immune system, or weaken it by spreading to the bone marrow. A weakened immune system may be unable to remove damaged  body cells , which increases risks for cancer development. QALI

3. Continua……………. Immune molecules, cells, tissues, and organs that work together to fight cancer normally provide immunity. Each immune component has a unique role, and when a foreign substance is recognized, the immune system responds in predictable ways to remove it – as long as functions are normal. The  components of the immune system  include the bone marrow, spleen,  thymus , circulatory system, mucosal-associated  lymphoid tissue  (MALT), and the  lymphatic system QALI

4. Continua………….. These organs and tissues work together, preventing infection. The structure and  cells of the immune system  includes primary and secondary organs, myeloid  immune cells , lymphoid immune cells, B-cell lymphocytes, T-cell lymphocytes,  effector cells , and regulatory cells. QALI

5. Molecular basis of the cancer Host The molecular basis of cancer is the result of mutations in genes that regulate cell behavior: Oncogenes :  These genes are normal genes that become mutated and activated. They can directly stimulate pathways that control cell growth, metabolism, and DNA repair. Tumor suppressor genes : These genes become inactivated by mutation. Cell cycle progression genes : These genes regulate the initiation of apoptosis. Genome integrity genes : These genes guard against damage.  QALI

6. Continua……………. Cancer is caused by multiple somatic mutations in a single cell and its progeny. These mutations can occur in a variety of ways, including: Point mutations : Small changes in sequence Partial deletions : Larger-scale changes Chromosomal translocations : Breakage and rejoining of the DNA helix Gene amplification events : Errors in DNA replication that cause extra copies of a gene to be present  QALI

7. Oncogenes Oncogenes are abnormal forms of normal genes (proto-oncogenes) that regulate various aspects of cell growth and differentiation. Mutations in these genes may result in direct and continuous stimulation of the pathways ( eg , cell surface growth factor receptors, intracellular signal transduction pathways, transcription factors, secreted growth factors) that control cellular growth and division, cellular metabolism, DNA repair, angiogenesis, and other physiologic processes . QALI

8. Continua……….. There are > 100 known oncogenes that may contribute to human neoplastic transformation For example, the  RAS  gene encodes the ras protein, which carries signals from membrane-bound receptors down the RAS- MAPKinase pathway to the cell nucleus, and thereby regulates cell division. Mutations may result in the inappropriate activation of the ras protein, leading to uncontrolled cell growth. The ras protein is abnormal in about 25% of human cancers . QALI

9. Continua…………. Other oncogenes have been implicated in specific cancers. These include HER2  (amplified in breast and gastric cancer and less commonly in lung cancer) BCR::ABL1  (a chimeric gene present in chronic myeloid leukemia and some B-cell acute lymphocytic leukemias ) CMYC  ( Burkitt lymphoma) NMYC  (small cell lung cancer, neuroblastoma ) EGFR  (adenocarcinoma of the lung) EML4ALK  (a chimeric gene present in adenocarcinoma of the lung), QALI

10. Continua…………….. Oncogenes typically result from Acquired somatic cell point mutations ( eg , from chemical carcinogens) Gene amplification ( eg , an increase in the number of copies of a normal gene) Translocations (in which pieces of different genes are joined to form a unique sequence) These changes may either increase the activity of the gene product (protein) or change its function . Occasionally , mutation of genes in germ cells results in inheritance of a cancer predisposition. QALI

11. Tumor suppressor genes Tumor suppressor genes, also known as anti-oncogenes, are genes that regulate cell growth and division to prevent cancer.  When these genes are mutated or inactivated, cells can grow out of control, which can lead to cancer. Genes such as  TP53 ,  BRCA1 , and  BRCA2  play a role in normal cell division and DNA repair and are critical for detecting inappropriate growth signals or DNA damage in cells. If these genes, as a result of inherited or acquired mutations, become unable to function, the system for monitoring DNA integration becomes inefficient, cells with spontaneous genetic mutations persist and proliferate, and tumors result. QALI

12. Continua……………….. As with most genes, 2 alleles are present that encode for each tumor suppressor gene. A defective copy of one gene may be inherited, leaving only one functional allele for the individual tumor suppressor gene. If a mutation is  acquired  in the functional allele, the normal protective mechanism of the second normal tumor suppressor gene is lost . QALI

13. Continua………. Inactive or altered p53 allows cells with abnormal DNA to survive and divide.  TP53  mutations are passed to daughter cells, conferring a high probability of replicating error-prone DNA, and neoplastic transformation results . TP53  is defective in many human cancers. QALI

14. Continua…………… BRCA1  and  BRCA2  mutations that decrease function increase risk of breast and ovarian cancers. Another example, the retinoblastoma ( RB ) gene encodes for the protein Rb , which regulates the cell cycle by stopping DNA replication. QALI

15. Continua……………. Mutations in the  RB  gene family occur in many human cancers, allowing affected cells to divide continuously. As with oncogenes, mutation of tumor suppressor genes such as  TP53  or  RB  in germ cell lines may result in vertical transmission and a higher incidence of cancer in offspring. QALI

16. Immune evasion Immune evasion is a defense mechanism that cancer cells use to avoid the immune system's detection and killing.  This allows cancer cells to grow and proliferate without restriction. Here are some ways that cancer cells evade the immune system: Downregulating cell-surface receptors . Cancer cells can reduce the expression of cell-surface receptors.  Expressing cell-surface proteins . Cancer cells can express proteins that interact with checkpoint proteins on immune cells.  QALI

17. Continua………… Hijacking the checkpoint protein mechanism . Cancer cells can use the checkpoint protein mechanism to inactivate immune cells.  Altering tumor-associated antigens . Cancer cells can alter tumor-associated antigens (TAAs) through mutations or epigenetic regulation of genes.  Altering the tumor microenvironment . Cancer cells can alter the tumor microenvironment (TME), which is made up of cytokines, chemokines , extracellular matrix, and numerous cell types.  QALI

18. Continua…………………. Silencing or downregulating Fas and Fas/ FasL signaling pathways. Cancer cells can silence or downregulate Fas and Fas/ FasL signaling pathways . Hijacking the checkpoint protein mechanism . Cancer cells can use the checkpoint protein mechanism to inactivate immune cells.  Altering tumor-associated antigens . Cancer cells can alter tumor-associated antigens (TAAs) through mutations or epigenetic regulation of genes.  QALI

19. Continua……….. Altering the tumor microenvironment . Cancer cells can alter the tumor microenvironment (TME), which is made up of cytokines, chemokines , extracellular matrix, and numerous cell types.  Silencing or downregulating Fas and Fas/ FasL signaling pathways. Cancer cells can silence or downregulate Fas and Fas/ FasL signaling pathways. QALI

20. Continua…………………. Immune evasion is  a defining feature of malignant tumors and is a major factor in tumor progression, recurrence, and metastasis. Here are some ways tumors evade immune surveillance: Tumor microenvironment (TME) : Tumors can alter the TME, which is made up of many cell types, cytokines, chemokines, and extracellular matrix. For example, hypoxia can lead to the expression of inhibitory checkpoints, such as PD-1, LAG-3, TIM-3, and CTLA-4.  QALI

21. Continua…………………… Glycocalyx : Tumors can modify their glycocalyx , a network of polysaccharides and glycosylated proteins, to shroud neoantigens and other ligands from the immune system.  Metabolites : Tumors can use metabolites like indoleamine -pyrrole 2,3-dioxygenase (IDO) and adenosine to escape immune clearance.  Inflammation : Tumors can produce inflammatory mediators like transforming growth factor type beta (TGF- β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF- α).  Immune checkpoint molecules : Tumors can express immune checkpoint molecules.  Antigen presentation mechanisms : Tumors can alter antigen presentation mechanisms.  QALI

22. Cytokines in cancer immune evasion Cytokines are molecular messengers that allow the cells of the immune system to communicate with one another to generate a coordinated, robust, but self-limited response to a target antigen. QALI

23. Continua……………. Glycocalyx : Tumors can modify their glycocalyx , a network of polysaccharides and glycosylated proteins, to shroud neoantigens and other ligands from the immune system.  Metabolites : Tumors can use metabolites like indoleamine -pyrrole 2,3-dioxygenase (IDO) and adenosine to escape immune clearance.  Inflammation : Tumors can produce inflammatory mediators like transforming growth factor type beta (TGF- β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF- α).  QALI

24. Continua…………….. Immune checkpoint molecules : Tumors can express immune checkpoint molecules.  Antigen presentation mechanisms : Tumors can alter antigen presentation mechanisms.  THE END QALI