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: – carcinoembryonic antigens -. Levels are increased during cells proliferation – in fetus, during malignancy, but also in another conditions: • alfa-feto protein (liver cancer), • carcinoembryonic antigen of gastrointestinal tract – mailny colon cancer). – Specific prostatic antigen – and many others 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 Systém (the Rule of 3 E) 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– frequently called „oncomarkers“- aplha-feto protein, carcinoembryonic antigen of gastrointestinal tract (CEA); speciphic prostatic antigen and many others….. • Monoclonal gammopathy • Immunophenotyping of lymphoid malignancies. B- cell development Immunomodulatory treatment of tumors • Check point (CTLA-4, PD-1) inhibitors (eg. nivolumab, ipilimumab) • Interferon alpha – lymphatic malignacies • BCG vaccine – bladder cancer • Tumour vaccination: Protective - vaccination against viruses (papillomavirus, HBV). Therapeutic -mainly using dendritic cells and other approches • Monoclonal antibodies • GVLR Graft-versus leukaemia reaction) after allogenic HSCT (Hematopoietic stem-cell transplantation). • Adaptive T-cell activation by cytokines – (IL-2), including TIL cells 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 Makes differnece between single immunoglobulin molecules 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 - paraprotein Electrophoresis of human serum Normal serum Paraproteins Imunofixation (antisérum IgG Lambda) Paraproteins • Monoclonal immunoglobulins in human serum. • Malignant – in myeloma • Benign – mainly in old people, patients with chronic inflammation, idiopatic (MGUS – monoclonal gammopathy of unknown significance) • Detected by imunoelectrophoresis, immunofixation