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immuneresponseagainsttumors-180607135635.pptx
- 2. Types of tumorantigens recognized by T cells Immune mechanisms of tumor rejection How tumors evade immune responses? Novel therapeutic approaches (immunotherapies)
- 3. Types of Tumorantigens Tumor-associatedantigens (TAAs) Tumor-specificantigens (TSAs)
- 4. T umor-associated antigens •expressed also onnormal cells . •normal cellular constituents but aberrant or dysregulated in tumors . T umor-specific antigens •expressed on tumor cells but not on normal cells . •individually unique or shared.
- 5. Tumor reactive CTLslines fromcancer patients Relevant peptide antigens . CD4Tcel lines fortumor antigens . SEREX(serologicalanalysisofrecombinantcDNAexpression) humoralimmuneresponsesintumorpatientsUsingantibodiespresentpatient’sserum.
- 7. 1 - Abnormally expressedbut unm utated cellular proteins : • Normal cellular proteins that are either overexpressed or whose expression is normally limited to particular tissues or stages of development but is dysregulated in tumor cells. • This aberrant expression may be enough to elicit such responses. • e.g. Self protein that are expressed only in embryonic tissues may not induce tolerance in adults .
- 8. 2-Productsofm utatedselfgenes: • Intrinsic genomicinstability of many cancers . • Tumor antigens may be produced by randomly mutated genes whose products are not related to the malignant phenotype . • Class I MHC pathway • Wide variety of genes may be mutated in tumor cells.
- 9. 3-O ncogenesandmutatedtumor suppressor genes: •Differ from normal cellular proteins . • Class I MHC pathway • Mutated Ras , Bcr/Abl fusion protein are two examples of oncogenes. • Mutated p53 is an example of mutated tumor expressed gene .
- 10. 4-Antigens ofO ncogenicviruses: • Theproducts of oncogenic virus: function as tumor antigens and elicit specific T cell responses • Virus-encoded protein antigens are found in the nucleus, cytoplasm or plasmamembrnare of the tumor cells. • most immunogenic tumor antigens. • shared by all tumors induced by the same type of virus
- 11. 4-Antigens ofO ncogenicviruses: DNA virusesRNA viruses
- 12. 4-Antigens ofO ncogenicviruses: RNA viruses •EBV: Bcell lymphomas, nasopharyngeal carcinoma • HPV : cervical carcinoma • Popovaviruse and adenovirus • HPV vaccine for cervical cancer in women • Vaccination against HepatitisBvirus
- 13. 4-Antigens ofO ncogenicviruses: • HumanTcell lymphotropic virus 1 (HTLV-1) • Adult Tcell leukemia/lymphoma (ATL) DNA viruses
- 14. 5-oncofetalantigens: • Proteins expressedat high levels in cancer cells and in normal developing fetal but not adult tissues • Silent during development, derepressed with malignant transformation • Increased in tissues and in the circulation in various inflammatory conditions • Markers for tumor diagnosis • Small quantities even in normal tissues . α-fetoprotein (AFP) Carcinoembryonic antigen (CEA:CD66) Oncofetal antigens
- 15. 6-Tissue-specificdifferentiationantigens : • Tumorsmay express molecules that are present only on the normal cells of origin and not on cells from other tissues • Melanoma antigens : targets of CTLs (Tyrosinase) • Lymphomas :CD10 and CD20
- 17. Tumors infiltrated withlymphocytes show less chance to survive than coated tumors . Lymphocytes proliferation in lymph nodes in some tumors point to an immune response tumors of those who take immune suppressors Regression of some tumors spontaneously “lymphoma ,mylanoma” High ratio of tumors of neonatals and olders who have weak immune reactions
- 19. studies have focusedon the antitumor response of CTLs because most tumors express class I Major Histocompatibility Complex (MHC) antigens and not MHC class II antigens. Antitumor immunity results from both:
- 20. Macrophage/Dendritic cell attackor antigen presentation CD8 cell-mediated cytotoxicity Antibody dependent cell mediated cytotoxicity (ADCC) Natural killer cells
- 25. It Doesnot recognize tumor cell via antigen specific cell surface receptor, but rather through receptors that recognize loss of expression of MHC I molecules, therefore detect “missing self” common in cancer. NK cells may also recognize specific proteins up-regulated and presented by cancer cells. Studies have indicated that cells in distress, including tumor cells, tend to express Rae1 and H60 ligands, which are not expressed in normal cells. The Rea1 andH60 ligands are recognized by the NKG2D receptor, which is regularly expressed by NK cells, activated CTLs and activated macrophages N K cell Target cell (infected or cancerous) Perforin and enzymes killer activating receptor
- 26. cell recognizes a Oncean NK cancer cell, it secretes the pore forming granule perforin into the region of the immunological synapse, thus causing target cells to lyse NK cells activate dendritic cells by producing IFN-γ (thus enhancing tumor immunogenicity), and also by providing DC with increased access to tumor antigens by killing activity.
- 28. Immune responses oftenfail to check tumor growth, because these responses are ineffective or because tumors evolve to evade immune attack The immune system faces a daunting challenge if it has to be effective against malignant tumors because: Immune responses must kill all tumor cells and tumors grow rapidly. Often, the growth simply outstrips immune defenses. Immune responses against tumors may be weak because many tumor antigens are weakly immunogenic, perhaps because they differ only slightly from self-antigens. Growing tumors also develop mechanisms for evading immune responses.
- 30. Evasion of ImmuneResponses by Tumors: Loss of T cell recognition: Antigen loss variants Loss of TAPs and other molecules involved in antigen processing Stop expressing class ∣ MHC molecules
- 31. Evasion of ImmuneResponses by Tumors: Explanations for why tumor cells that have lost HLA class I are not destroyed by NK cells ? loss or down-regulation of NKG2D ligands expression lack of stimulatory cytokines and secretion of immunosuppressant cytokines producing the matrix metalloproteinase 9, which results in ICAM-1 shedding and resistance to NK cell killing
- 32. Tumor antigensmay be inaccessible to the immune system: Antigen masking: tumor cells express more of glycocalyx molecules than normal cells do. The cell surface antigens : hidden from the immune system by glycocalyx molecules (sialic acid-containing mucopolysaccharides) Glycocalyx molecule (sialic acid- containing mucopolysaccharide s) Evasion of Immune Responses by Tumors:
- 33. Tumor may engagemolecules that inhibit immune response: Involvement of PD-L1 , CTLA-4 Secreted products of tumor cells may suppress anti- tumor immune response: TGF-β,secreted in large quantities by many tumors that Inhibits the proliferation and effector functions of lymphocytes and macrophages Evasion of Immune Responses by Tumors:
- 34. Evasion of ImmuneResponses by Tumors: Tumor-associated macrophages (TAMs):
- 35. Evasion of ImmuneResponses by Tumors: Regulatory T cells: may suppress T cell responses to tumors: A population of T cells that regulate the activation or effector functions of other T cells and may be necessary to maintain tolerance to self antigens. Regulatory T cells express 𝐂𝐃𝟒+and CD25 Depletion of regulatory T cells in tumor-bearing mouse enhances anti-tumor immunity and reduces tumor growth
- 36. Regulatory Tcells:
- 37. the Fascounter attack :
- 39. is the useof immune system to reject cancer . What about Chemotherapy?
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- 41. Naked mAbs Conjugated mAbs: Radiolabelled Chemolabelled Immunotoxin
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- 46. • Therapeutic cancervaccines trigger the immune system to recognize and attack certain markers, or antigens, present on or in cancer cells . • Unlike traditional vaccines, which help to prevent disease, therapeutic cancer vaccines treat disease that is already there . • Cancer vaccines often require additional substances called adjuvants for optimal effectiveness .
- 47. Cancer Vaccines : Antigen vaccines Dendritic cell vaccines DNA vaccines .
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- 55. In late 1800’sDr William Coely first noted that getting an infection after surgery seemed to help some cancer patients . He began treating cancer patient’s by infecting them with certain kinds of bacteria , which came to be known as Coely toxins .
- 56. • Oncolytic virusesare viruses that directly kill (“lyse”) cancer cells and can also activate cells of the immune system, such as dendritic cells and T cells, to target and eliminate cancer throughout the body . • Sometimes, Oncolytic viruses are genetically modified to produce immune-stimulating chemicals, or to make them more specific for cancer cells . • Oncolytic virus immunotherapies are often combined with other types of cancer immunotherapies, including therapeutic cancer vaccines and mAb therapy
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- 60. Cytokines are messengermolecules that help control the growth and activity of immune system cells interleukins (IL) help immune cells grow and divide more quickly interferons (IFN) boost the ability of certain immune cells to attack cancer cells