Immune Systems and Cancer Lecture 2024 PDF

Immune system and cancer Associate Professor Li Zhang School of Biotechnology and Biomolecular Sciences Room 4106, E26 [email protected] Learning outcomes After successfully completing this learning activity, you should be able to: Understand how cancer cells avoid the attack from the immune syste...

Immune system and cancer Associate Professor Li Zhang School of Biotechnology and Biomolecular Sciences Room 4106, E26 [email protected] Learning outcomes After successfully completing this learning activity, you should be able to: Understand how cancer cells avoid the attack from the immune system Describe various types of cancer immunotherapy Understand cancers of the immune system Describe the examination of immune cell clonality The dual roles of the immune system in cancer The immune system plays an important role in preventing cancer (immune surveillance). People with immunodeficiency have increased cancer risk. -Organ transplant recipients treated with immunosuppressive drugs are more prone to cancer development. -Infection of HIV leads to elevated risk of cancer. On the other hand, chronic inflammation increases the risk of cancer. Mechanisms by which cancer cells avoid immune attack Low MHC class I molecules. Cancer cells down regulate MHC class I, many cancer cells lose about 90% MHC class I antigen presentation, so it can no longer be recognized by specific CD8+ cytotoxic T cells. NK cells? When dendritic cells present tumor antigens, induce T cell toleration due to lack of co- stimulatory signals. Antigenic modulation (no immunogenic antigens expressed). Fibroblasts in tumors produce collagen that create a physical barrier (tumor nests) to prevent the interaction of immune cells with tumor cells. Cancer cells create an immune suppression environment. -Secrete TGF-β, IL-10 and indoleamine 2,3-dioxygenase (IDO) to inhibit T cells. -Cancer cells express PD-L1. Immune checkpoint proteins PD-1 (programmed death-1) and PD-L1 Front. Cell Dev. Biol., 21 July 2020 Volume 8 - 2020 | https://doi.org/10.3389/fcell.2020.00672 Immune checkpoint proteins CTLA-4: cytotoxic T-lymphocyte-associated protein 4 Co-stimulatory molecules Co-inhibitory molecules Cancer Immunotherapy Strategy Mechanism Immune checkpoint blockade: AntiCTLA-4, anti-PD1, anti-PD-L1 antibodies. Unleash pre-existing anticancer T cell responses and possibly triggers new anticancer T cells. Adoptive cellular therapy: T cells are taken from the patients, genetically modified to generate chimeric antigen receptor T cells (CAR T cells). The CARs recognize and bind to specific proteins on the surface of cancer cells. Vaccine Combination immunotherapy (immune checkpoint blockade as the backbone). Generating T cells attacking antigens on cancer cells. Stimulating the host immune response against cancer cells. LEUKAEMIAS AND LYMPHOMAS Leukaemia: cancers of blood cells (most of the cases are white blood cells cancer), originating in blood or bone marrow. Lymphoma: cancers of lymphocytes, forming tumor in lymphoid organs such as lymph nodes. Myeloma (multiple myeloma): cancers of plasma cells. Most of the cancer cases are from B cells. Incidence in Australia Leukaemia: About 3000 new cases/year. Most of the cases are CLL (chronic lymphocytic leukaemia). Lymphoma: About 4500 new cases/year, about 90% are NHL. Myeloma: about 1200 new cases/year. The cause? 1. Exposure to radiation 2. Exposure to certain chemicals 3. Viruses Burkitt’s lymphoma is linked to Epstein-Barr viral infection Symptoms 1.Bleeding (nose, gum, bruise easily) 2.Frequent infections 3.Bone pain 4.Fever 5.Lumps caused by swollen lymph nodes 6.Splenomegaly 7.Weakness, fatigue, general decrease in energy Common used Laboratory Tests 1. Complete and differential blood count 2. Bone marrow aspiration 3. Lymph nodes aspiration/biopsy 4. Immunophenotyping 5. Monoclonality 5. Cytogenetics 6. X-ray to check bone Treatment 1. 2. 3. 4. Chemotherapy Radiotherapy Biological agents Bone marrow transplantation Many cases in children and young adults are cured Some cases in older patients are slowly progressive and do not need treatment LEUKAEMIA Lymphocytic ALL CLL Myeloid AML There are other types. Most cases of leukaemia involving B cells CML LYMPHOMA HODGKIN’S LYMPHOMA (HL) Thomas Hodgkin 1798-1866 Involving B cells Five subtypes of HL About 10% lymphoma cases are HL. Non-HODGKIN’S LYMPHOMA (NHL) Involving either B or T cells (80% of NHL involving B cells) There are more than 30 subtypes of NHL HODGKIN’S LYMPHOMA (HL) Involving B cells Five subtypes of HL http://upload.wikimedia Myeloma (multiple myeloma) 1. Cancer of plasma cells (plasmacytoma). 2. Producing large amounts of monoclonal antibodies (myeloma proteins, or M proteins) IgG (most common), IgA, IgD, IgE or IgM May produce a large amount of light chain protein (light chain myeloma) Does not increase an individual’s immunity Decreases the development of other immune cells The malignant plasma cells produce osteoclasts-activating factors--stimulating osteoclasts to break down bone structure. B LINEAGE MALIGNANCIES Stem cell Developing B cell Immature B cell ACUTE LYMPHOBLASTIC LEUKAEMIA Long-lived plasma cell IgM Mature B cell IgM IgD Plasma cell CLL LYMPHOMA Germinal centre Activated B cell IgM Memory cell MULTIPLE MYELOMA IgG IgA IgE Bone Marrow Class-switching IgG IgA IgE Somatic hypermutation Secondary lymphoid tissue Immunophenotyping Immunophenotyping: a test used to identify cells based on markers (antigens) present on the cell’s surface, cytoplasm or nucleus. CD45: Leucocyte common antigen (have isoforms) B cell: CD19, CD20 B cell and plasma cell: immunoglobulin kappa and lambda light chains T cell: CD3, CD4, CD8, CD5, CD7, CD2 … MALIGNANT B CELLS EXPRESS STANDARD B CELL SURFACE MARKERS Normal B cells - pos for B cell markers CD19 and CD20 CD19 B-cell lymphoma also pos for CD19 and CD20 CD20 MONOCLONALITY Assessment of monoclonality in B cell malignancy: Flow cytometry staining of surface light chains Assessment of monoclonality in T cell malignancy: PCR detection of T cell receptor genes KAPPA/LAMBDA RATIO Each B cell or plasma cell makes only one antibody, and its 2 light chains are identical. Therefore the surface and secreted antibody of each one B cell or plasma cell is either kappa or lambda. The ratio of B cell/plasma cells with kappa and lambda: 2:1 Polyclonal response (eg infection) kappa and lambda ratio = 2:1 DETECTION OF B CELL CLONALITY BY LIGHT CHAIN STAINING B cells are blue NORMAL Polyclonal B cells - mixture of kappa pos and lambda pos B cells ABNORMAL Most B cells are a monoclonal lambda pos B cell population kappa lambda MONOCLONALITY Assessment of monoclonality in multiple myeloma, – Intracellular staining of light chains – Electrophoresis/immunofixation to detect antibodies or light chains DETECTION OF INTRA- CELLULAR LIGHT CHAIN STAINING IN PLASMA CELLS purple cells are plasma cells red cells are lymphocytes Polyclonal plasma cells in a reactive bone marrow lambda Monoclonal kappa pos plasma cells in a case of multiple myeloma Plasma cells are more abundant in multiple myeloma, a cancerous disorder, than in reactive bone marrows. kappa IMMUNOFIXATION (IF) Electrophorese the serum or urine in several different tracks Add specific antibodies to immunoglobulin components (such as κ or λ) to each track. Wash the gel extensively – only immune complexes containing the appropriate immunoglobulin components remain (soluble Ag +Ab, form precipitates) (are “fixed” in the gel) Stain for proteins - the stain will reveal the fixed proteins Compare with track where all serum proteins are stained Monoclonal plasma cell disorder Normal Whole serum IF for  IF for  broad smear narrow band, a “paraprotein” or “M protein” The band contains  but not  Which of the following are reasons why B cell malignancies are more common than T cell malignancies? (more than one may be correct) 1. B cells are produced in larger numbers than T cells 2.Developing B cells undergo V(D)J recombination, which involves DNA strand breakage, whereas developing T cells donot. 3 In B cells, somatic hypermutation (SHM) can cause mutations in proto-oncogenes, but SHM does not occur in T cells. 4 In B cells, but not T cells, class switch recombination, which involves DNA strand breakage, can lead to incorrect recombination. 5 Mature B cells divide in the secondary lymphoid tissue, whereas mature T cells do not.