Immune response against tumors Tumor antigens •Tumor-speciphic antigens – new antigens which develop in tumor cells. •Tumor associated antigens – „normal“ body antigens, but their expression is markedly increased in malignancies (e.g. carcinoembryonic antigens). Tumor antigens in different types of tumors •Virus-induced tumors: Antigens are usually virus-speciphic. •Carcinogen-induced: no inducer-related specificity of antigens. •Spontaneous tumors: antigens are usually very variable. PhD2005-I Cancer immunoedition (Du nn GV, Bruce AT, Ikeda H, Old LJ, Schreiber RD: NatureImmunology 2002; 3:991-998) Possible Consequences of Interaction Tumor-Immune System Immune Response to Tumors •Cytotoxic T-lymphocytes (Tc) •Natural killer (NK) cells •Antibody-dependent cellular cytotoxicity (ADCC) •Activated macrophages •Role of dendritic cells •Antibody response – minor importance • Protective Mechanisms of Tumors •Low immunogenicity of tumor antigens •Low expression of HLA I molecules •Antigenic modulation •Immunosuppression – prostaglandins, IL-10 and TGF-b like cytokines, stimulation of Ts lymphocytes •Large tumor mass • Immunodiagnostic of tumours •Detection of tumor associated/speciphic antigens- if easily detected in plasma/serum – frequently called „oncomarkers“: aplha-feto protein, carcinoembryonic antigens, speciphic prostatic antigen and many others….. •Monoclonal gamapathy •Immunophenotyping of lymphoid malignancies. • • B- cell development • Vývoj B-lymfocytů Immunomodulatory treatment of tumors •Adaptive T-cell activation •Check point (CTLA-4, PD-1) inhibitors (eg. nivolumab, ipilimumab) •Cytokines – IL-2 •Interferon alpha •BCG vaccine •Tumour vaccination: –Protective - vaccination against viruses. –Therapeutic -mainly using dendritic cells and other approches •Monoclonal antibodies •GVLR Graft-versus leukaemia reaction) after allogenic HSCT (Hematopoietic stem-cell transplantation). • Antitunour vaccines http://www.frontiersin.org/Journal/10.3389/fonc.2011.00022/full TIL – tumor infiltrating lymphocytes http://www.nature.com/nri/journal/v12/n4/fig_tab/nri3191_F1.html Monoclonal Antibodies in Oncology •Anti-CD20 (rituximab) directed against malignant B-cells. •Anti-CD52 – T-cell lymphoma, chronic lymphatic leukemia •Monoclonal antibodies against receptors for growth factors: ERBB2(HER 2 receptor) epidermal grow factor... •Monoclonal antibodies against negative check points of T-cells – PD-1, CTLA-4 • Checkpoint blockers https://www.hindawi.com/journals/scientifica/2013/857519.fig.001.jpg Other approaches •Blockade of BTK (Burton's tyrosine kinase, necessary for B-cells development ) – ibrutimib •Blockade of the intracellular signalling pathways (e.g. kinase inhibitors) •CAR chimeric antigen receptor T cells – antigen specific part of monoclonal antibody attached to T-receptor intracellular chain + other stimulatory molecules. • CAR http://www.discoverymedicine.com/Jae-H-Park/2010/03/30/adoptive-immunotherapy-for-b-cell-malignanci es-with-autologous-chimeric-antigen-receptor-modified-tumor-targeted-t-cells/ Monoclonal gammopathy and myeloma • schema3-01.png Clonal selection theory Effector cells antigen Memory cells Elimination of autoreactive clones Blood and periperal lymphatic organs expansion death death Myeloma •Tumor that evolves from plasma cells •Paraprotein (monoclonal gammopthy) in serum •Increase in plasma cells in bone marrow •Kidney failure •Pathologic fractures •Secondary immunodeficiency Myeloma cells myeloma1 Electrophoresis of human serum Normal serum Paraproteins Electrophoresis - paraprotein M komponenta schema6a-01.png Immunodiffusion-I Gel Ags diffuse into gel setting up a concentration gradient Abs diffuse into gel setting up a concentration gradient schema6b-01.png Immunodiffusion - II Gel Large aggregates form at the place of equimolar concentrations of Ag & Ab Imunoelecrophoresis figc6_1 Imunoelectrophoresis (IgG Kappa praprotein) myeloma2 Imunofixation (antisérum IgG Lambda) myeloma3 Paraproteins •Monoglonal immunoglobulins in human serum. •Malignat – in myleoma •Benign – mainly in old people, patients with chronic inflammation, idopatic (MGUS – monoclonal gammapathy of unknown significance) •Detected by imunoelectrophoresis, immunofixation