The Immune System & Cancer Flashcards
Describe cancer cells.
-mutations triggered by chemicals, radiation, viruses, inherited defects in regulatory genes
-cells proliferating uncontrollably by growing clone of cells that develop into tumor/neoplasm
-mechanisms of tumor suppression: DNA repair, cellular senescence, apoptosis etc
Describe the different types of tumor neoantigens.
- Mutated proteins
-altered versions of normal proteins
-melanoma associated antigen recognized by T cells (MART1)
-encoded by mutated genes & not found on normal cells
-single tumor can express many neoantigens - Differentiation antigens
-expression of antigens not normally found in adults (fetal only)
-oncofetal antigens
-carcinoembryonic antigen (CEA/CD66e) in GI tumors - Overexpressed cellular proteins
-expression for longer times or at diff locations
-abnormal high levels of expression (PSA in prostate cancer) - Oncogenic viruses antigens
-response against tumor
-FOCMA in FeLV cats/Mareks disease in chickens - Cancer/testis antigens
-tumor antigens expressed in testes & various tumors
Describe immune surveillance.
-1909 Paul Erlich
>host defense prevent neoplastic cells from developing into tumors
-1953 Gross & Foley
>tumor stimulated IR
-1950s MacFarlene Burnet
>tumor cell neoantigens induce IR against cancer
>immune surveillance theory
Describe cancer immunoediting.
2002 Dunn & Schreiber
1. Elimination phase
-tumor cells killed by NK, CD4 & CD8 T cells
2. Equilibrium phase
-IS unable to destroy tumor
3. Escape phase
-detectable tumors
Describe the immune surveillance elimination via the innate IS.
- Neutrophils
-make TAIL (TNF related apoptosis inducing ligand)
-stim apoptosis in tumor cells - NK cells
-failure to express MHCI
-express non classical molecules (MICA/MICB)
-express NKG2D = bind MICA/MICB on tumor cells - Macrophages
-classically activated M1 macrophage kill tumor cells
-recognize DAMPs from dying tumor cells thru macrophage TLRs
-activate macrophage by IFNy made by tumor specific T cells
-make NO
*M2 macrophages = promote tumor growth thru secretion of vascular endothelial growth factor (VEGF) & TGF-B
>can gen anti inflammatory environment within tumor
Describe the immune surveillance elimination via the adaptive IS.
- CD8 T cells
-specific for tumor peptides presented on MHCI
-directly lyse tumor cells using perforins & granzymes - CD4 T cells
-activated by APCs presenting tumor antigens leading to direct/indirect destruction of tumor - NKT cells
-recognize Ag presented by non classical MHC I on tumor cells
*tumor bearing hosts make Ab against tumor antigens
>Ab kill tumor cells by activating complement or by antibody-dependent cell-mediated cytotoxicity
Describe equilibrium.
-tumor cells remain but dont progress
>not completely eliminated/dont proliferate
Describe immunological escape mechanisms.
-similar to self
-no PAMPS
-not all cells express same neoantigens
-switch off T cell response
-tumor derived IL4, IL6, IL10, TGFB, PGE2, IDO
-T cell checkpoint molecules
>CTLA4, PDL1
>anergy
Describe tumor escape: immunosuppression.
- TGFB
-induce tumor cell prolif & angiogenesis
-suppress element of host anti tumor IR - Indoleamine 2,3 dioxygenase (IDO)
-suppress T cell prolif - Galectin 1
-stim angiogenesis - PDL1
-slow down IR
Describe transformed cells.
- Downreg molecules that can facilitate T cell or NK mediated attack
-ex. Loss of MHC, Tc epitopes, ICAM1 - Upreg/secrete molecules that can kill lymphocytes
-ex. FasL - Anergize T cells that infiltrate tumor
-ex. PDL1, PDL2, IL10, IDO
Describe tumor immunotherapy via nonspecific immune stimulation.
-cytokine therapy (interferons, TNFa, IL2, IL4)
-T-LAK cells
>gen by taking peripheral blood lymphocytes & activating them w IL2 & returning them IV
-microbial products
-checkpoint inhibitors
Describe the principles of immune checkpoint therapy.
- CTLA4
-inhibitory receptor expressed on T cells
-ligand = B7 expressed on cancer cells
-blocking of CTLA4 by antibodies = cytotoxic T cells against tumor cells - PD1
-blocks tumor cell apoptosis by binding to ligand PDL1
>allows cytotoxicity & apoptosis
Describe passive VS active immunization.
- Passive
-monoclonal Ab against tumoral Ag - Active
-chemically modified tumor cells
-vaccine against oncogenic viruses
EX: FeLV, Mareks disease