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07 - March 5, 2013.docx

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University of Toronto St. George

FINAL EXAM – tend to do worse – responsible for all the lecture material and the second half of the student presentations Cure cancer using immune system Two goals for immunotherapy - Induce clinically effective antitumour responses o Do not want antitumour immunity to attack normal cell – just target cancer cells - Establish antitumour immunological memory o Memory effect – improve patients’ quality of life – multiple doses Immunosurveillance Burnet thought that immune system should be able to see tumours – Stutman – but his mice was nude mice – later on, nude mice have lots of NK cells Schreiber and others – lack B, T, and NK cells – demonstrated a difference using these mice Immune status of mice – induce tumour using carcinogen in both immunodeficient and immunocompetent mice – watch mice day by day for tumour formation First 80 days, no difference Past that, see difference – tumour formation in immunodeficient mice; after 120 days, tumours also start to form in immunocmpetent mice Concluded that immune system can watch the tumour cells and suppress formation of tumours Difference in the tumours formed in the different kinds of mice – Tumour cell from both types of mice – nucleated those tumours into immunocompetent mice – have tumours, and enucleated into wild-type – see tumour formation – but tumours did not progress Then he also harvest tumour from immunodeficient mice – nucleated tumours onto immunocompetent mice – now half of tumours did not make tumours, cancer progress – received tumours from immunodeficient mice, tumour formed, but regressed Difference in QUALITY of tumours High immunogenicity – so immune system able to reject the tumours Concluded immunoediting Transformed cells – genetic problem, irradiation, virus infection, radiation – these intrinsic factors can cause tumour formation In most cases, the tumours can be eliminated – using the power of adaptive immunity and innate immunity – in nude mice, NK cells able to reject tumours – using knockout mice, molecules required for elimination of tumours – elimination – tumours removed and see clinically relevant tumours formed – no tumour formation in patient Problem – this does not always happen Due to second mutation, etc, equilibrium phase – tumour cells dormant and the host system tries to edit the tumours so balance between tumour formation and immune host system – once the balance worn by tumour side, called tumour escape and lots of immune – tumour environment to promote formation of tumour – clinically obvious cancer cells The three E’s of cancer immunoediting Elimination – immunosurveillance – Low immunogeneicity – Escape phase – patients admitted to hospital – tumour escape and now tumour is resistant to immune system, evade immune system, see clinically detectabletumours – now immune system in body cannot control tumours and patients need treatment Clear evidence that immune system can watch the tumours Basis for cancer immunotherapy T cells can recognize antigens Spontaneous antitumour T cell responses – human T cells can detect tumours T cell tumour infiltration – T cells can sense and locate tumours and can traffick to the tumour side – good evidence that T cell can see the tumours Tumour-associated antigens Preferentially expressed by tumour cells – normal cells should lack expression of these peptides MAGE family – melanoma antigen Tuour antigen allows for detection of antitumour T cells – using technology – we’re able to identify these peptide-specific T cells – and then able to do tumour-specific immunotherapy that doesn’t attack or recognize normal – if immunity recognize normal cells – healthy issues –when patient is autoimmune disease – Various types of tumour-associated antigens Obviously, antigen is target – If the protein goes thorugh post-tanslational modification, this may serve as antigen EBV virus – cause cancer – healthy donors do not usually express the health antigen MHC/peptide tetramer – complex of one MHC, one beta macroglobulin, - not sufficient to bind T cell receptor Dimer is required to bind the TCR – but to ehance assocaiton between TCR and this complex, use tetramer or pentamer or etc. – using these reagents, able to detect T cell receptor expressed by T cell – able to identify the peptide-specific T cells Ex vivo detection of melanoma-specific T cells Melan-A = melanoma antigen restricted by HAL Tumours can be recognized by T cells, which can specifically recognize tumour cells that express HLA and peptide Immune contexture in human tumours – tumour should have lymphocyte that can affect tumour – serve as good evidence that T cell can recognize tumours – Vasculature with tumours surrounded by various lymphocytes Pathologist: any correlation between the number/quality of lympohcytes and patient prognosis? Memory T cells – good prognosis for the patient Location – T cell need to localize at the centre of the tumour or invasive margin Density and function also important Association of T cell infiltrates with prognosis in various types of cancer Under some circumstances, these T cells promote tumour formation or negatively affect prognosis of cancer patient Association of T cell infiltrates with prognosis in cancer Renal cell carcinoma – the existence of CD8 T cell in this cancer is not good, but this is the only one exception – most studies, CD8 T cells is good marker for overall survival of patient Treg is not good marker; TH17 sometimes cause cancer, sometimes suppress cancer – usually TH2 negatively affect prognosis; once TH2 is dominant, TH1 less dominant, work well to eliminate cancer Strong rationale to support that cancer immunotherapy should work in some cancer patients to eliminate cancer Various approaches of cancer immunotherapy Immunomodulators; Generation of potent antitumour immune response requires multiple steps Multiple steps required to induce clinically effective antitumour responses in the patient – multiple steps – first thing, T cell responses generated, but ineffective alone; T cells needs to learn to attack tumours, for which APC (best are DC) are necessary to educate T cells to attack tumours, not normal cells DC recognize tumour cells; DC uptake tumour antigen from tumour, process and present; best way for DC to recognize tumour DC activated by environment Tumour antigen uptaken and processed and presented by APC – deliver signal to TCR – T cell ready to attack tumour cells T cells can recognize tumour cells – T cells also express many immunoaccessory molecules – immunoaccessory molecules not always activating, can negatively affect tumour activation (called co- inhibitory molecule, like PD1 and CTLA4) – immunotherapy targeting these molecules may work Tumours and T cells in environment that is suppressing T cell responses (anti-tumour responses) and partly mediated by Treg cells and MDSC suppressive cells When MDSC see tumour cells, suppress antitumour responses – end up with immune system ineffective at riding body of tumour Immune modulators – two different phases IDO – can induce Interferon gamma – critical molecule secreted by CD8 T cells, which is good marker for good prognosis of cancer – CTL secreted Interferon gamma – induced IDO (negative) – always cross-talk between tumour cells and T cells and environment – Tryptophan is aminase – deplete it by IDO – inhibit T cell proliferation – this is bad to suppress T cell function Need to get rid of IDO Suppression of immune response by IDO-expressing cells CDs can also express IDO – IDO expressed in tumour cells may suppress function and proliferation of CD8 T cells – need to block this signal At the same time, cross-talk between IDO-negative T cells and lymphocytes – even if IDO DC can block the good interaction between IDO- DC and lympohcytes – need to get rid of IDO positive DC Correlation of IDO-expressing tumours with patient survival – existence of IDO positive cells never affects overall survival – evidence that IDO is bad 1-MT – is IDO inhibitor – in vivo model of mouse – delay tumour progression – in vivo data to support human clinical trials – now currently tested in clinical trials Generation of potent antitumour – target immunosuppressors – two major types – immunsuppressive that Treg are myeloid derived suppressor cells Myeloid cell
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