Mechanisms of tumor evasion from the immune response
Tumor cells have developed various mechanisms to escape immune surveillance
• CD8+ cytotoxic T cells are a fundamental element of anti-tumor immunity. Their TCR receptors recognise antigens presented by MHC class I and when bound, the Tc cell triggers its cytotoxic activity. MHC I are present on the surface of all nucleated cells. However, some cancer cells lower their MHC I expression and avoid being detected by the cytotoxic T cells. This can be done by mutation of MHC I gene or by lowering the sensitivity to IFN-γ (which influences the surface expression of MHC I). Tumor cells also have defects in antigen presentation pathway, what leads into down-regulation of tumor antigen presentations. Defects are for example in Transporter associated with antigen processing (TAP) or Tapasin On the other hand, a complete loss of MHC I is a trigger for NK cells. Tumor cells therefore maintain a low expression of MHC I.
• Another way to escape cytotoxic T cells is to stop expressing molecules essential for co-stimulation of cytotoxic T cells, such as CD80 or CD86.
• Tumor cells express molecules to induce apoptosis or to inhibit T lymphocytes:
Expression of FasL on its surface, tumor cells may induce apoptosis of T lymphocytes by FasL-Fas interaction
Expression of PD-L1 on the surface of tumor cells leads to suppresion of T lymphocytes by PD1-PD-L1 interaction
• Tumor cells have gained resistance to effector mechanisms of NK and Cytotoxic CD8+ T cell:
by loss of gene expression or inhibiton of apoptotic signal pathway molecules: APAF1, Caspase 8, Bcl-2-associated X protein (bax) and Bcl-2 homologous antagonist killer (bak).
by induction of expression or overexpression of antiapoptotic molecules: Bcl-2, IAP or XIAP.
Tumor cells have developed various mechanisms to create immunosuppressive tumour microenvironment
• Production of TGF-β by tumor cells and other cells (such as Myeloid-derived suppressor cell) leads to conversion of CD4+ T cell into suppressive regulatory T cell (Treg) by a contact dependent or independent stimulation. In a healthy tissue, functioning Tregs are essential to maintain self-tolerance. In a tumor, however, Tregs form an immunosupresive microenviroment.
• Tumor cells produce special cytokines (such as Colony-stimulating factor) to produce Myeloid-derived suppressor cell. These cells are heterogenous collection of cell types including precursors of Dendritic cell, Monocyte and Neutrophil. MDSC have suppressive effects on T-lymphocytes, Dendritic cells and Macrophages. They produce immunosupressive TGF-β and IL-10.
• Another producer of suppresive TGF-β and IL-10 are Tumor-associated macrophages, these macrophages have mostly phenotype of alternatively activated M2 macrophages. Their activation is promoted by TH type 2 cytokines (such as IL-4 and IL-13). Their main effects are immunosuppresion, promotion of tumor growth and angiogenesis
• Tumor cells have non-classical MHC class I on their surface, for example HLA-G. HLA-G is inducer of Treg, MDSC, polarise macrophages into alternatively activated M2 and has other immunosuppresive effects on immune cells.
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