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. 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 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-malignancies-with-autologous- chimeric-antigen-receptor-modified-tumor-targeted-t-cells/ Monoclonal gammopathy and myeloma 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 Electrophoresis of human serum Normal serum Paraproteins Electrophoresis - paraprotein Immunodiffusion-I Gel Ags diffuse into gel setting up a concentration gradient Abs diffuse into gel setting up a concentration gradient Immunodiffusion - II Gel Large aggregates form at the place of equimolar concentrations of Ag & Ab Imunoelecrophoresis Imunoelectrophoresis (IgG Kappa praprotein) Imunofixation (antisérum IgG Lambda) 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