14. Antitumor immunity; immunodeficiency Flashcards
How tumors escape control
- Fast proliferation
- Mutations
- High diversity (“mini evolution”)
Oncogenes
- encode proteins that can induce malignant transformation
- viral (v-onc)
- exons
- modulate proliferation/apoptosis
- well-conserved structures
proto-oncogenes -> function in physiologically intact cells, cellular (c-onc), exons or introns
Potential sources of tumor ags
Oncogene product
- mutation in RAS codon 12 (pancreatic cancer)
- bcr/abl proten (CML)
Embryonic proteins
- MAGE family (melanoma, brest cc.)
Viral proteins
- EBV (Hodgkin’s lymphoma)
- Hep. B (hcc)
Tissue specific ag
- Tyrosinase (melanoma)
Mutant tumor suppressor protein
- p53 (many cancers)
Idiotypic epitopes
- TCR idiotypes (T cell lymphoma)
Types of tumor ags
TSA - tumor cells only, presented with MHCI, evoke Tcyt response (FasL)
TAA - tumor cells and some normal cells
Production of TSA
- Chemical carcinogens
- X-rays
- Somatic mutations
MAGE-1
= melanoma ag-encoding gene
In:
- 40% melanomas
- 20% breast cc.
- 30% lung small cell cc.
- embryonal protein
- expression is de-repressed in tumors
- present in some normal cells as well (e.g. testis)
TAAs
- Oncofetal ags
- Differentiation specific ags (DSA)
Oncofetal ags
- Normally expressed during a specific phase of embryogenesis
- Practically in mature, differentiated tissues
- Not immunogenic
- No functional role in tumor immunity
- Significance: diagnostic, prognostic markers
- Serum cc. correlates with tumor mass, level of differentiation and response to therapy
Ideal tumor markers
- Specific for tumor type
- Released only in response to tumor
- Results proportional to tumor mass
- Quantitatively reflects tumor response
- Elevated even with low tumor burden
Carcinoembryonic ag (CEA)
- discovered in adenocc of colon
- group of heterogenous glycoproteins (mw. 200 kD)
- Normally in embryotic and fetal digestive tissues
- Detected by RIA or IHC
- Elevated (over 5ng/ml) in GI, breast, pancreas, lung tumors and alcoholic cirrhosis, inflammations
alpha-fetoprotein (AFP)
- increased in hcc and malignant teratomas
- increased in serum in metastatic tumors in liver and acute hepatitis
Host immune response to tumor (experimental)
- Colony inhibiton of tumors by sensitized lymphocytes
- Tumors extract induce lymphocyte blast transformation
- Lymphocyte-enhanced cytotoxicity
- Macrophage-enhanced phagocytosis
Host immune response to tumors (clinical)
- Spontaneous regression
- Regression of tumors in response to sublethal doses of chemotherapy
- Regression of metastasis from resection of primary tumor
- Mononuclear cell infiltration
- High incidence of tumor after clinical immunosuppression
- High incidence of tumor in immunodeficiency
- Increased incidence of tumor in aging
Cellular effectors that mediate immunity
Tcyt -> protect against virus-associated neoplasms (e.g. EBV)
NK ly -> lysis of tumor cells without prior sensitization via NKR-P1
(only tumor cells without MHC are lysed as activity is blocked by Ly49 receptor that recognizes MHCI)
IL-2 (from T cell) -> NK lymphocytes can lyse a variety of tumors (complement)
Macrophages -> selective cytotoxicity against tumor cells (ROS, TNFalpha)
Humoral mediators against tumors
Activation of complement
Induction of ADCC by NK lymphocytes
Immunodeficiencies role in cancer development
Congenital immunodeficiency -> 5% develop cancer (200x risk)
Immunodepressed patients -> 80x risk
- AIDS
- Lymphomas
- Chronic infections mononucleosis
- Malignant lymphomas
How tumors escape immunity
- Shedding of tumor ags (soluble)
- Loss of HLA ags
- No costimulation -> anergic T-cell -> apoptosis of T-cell
- Selective outgrowth of ag negative variants
- Expression of local inhibitory molecules (e.g. TNFbeta, FasL)
- Immunosuppression (chemicals, radiation, TGFbeta)
-> only NK lymphocytes can detect them, but these are no present everywhere
Effects of NK-lymphocytes
Activation of killer inhibitory receptor (KIR) on NK -> No apoptosis of target cell
Activation of killer activated receptor (KAR) on NK -> Apoptosis of target cell
Failure of immuno response to tumor
- Tumors in areas not accessible to effector cells (e.g. eye, CNS)
- Antigenic modulation: ags of tumor cells may undergo several changes
- Blocking factors: immune complexes or cytophilic abs can mask tumor ags/prevent binding by effector cells or lytic abs
Antitumor immunotherapy
- Tumor cell vaccines - increasing antitumor T cells with autologous or allegenic tumor cells
- Immunization with tumor-specific peptides - only for tumors where TAA have been cloned and peptides synthesized
- Cytokine therapy - increasing the levels of some cytokines (Il-2, IFN, CM-CSF, IL-7, IL-12)
Problems:
- short life-time
- toxicity
- non-specific cytokines
- Monoclonal abs - to deliver immunotoxins, radioisotopes. Bivalent abs recognize both T cells and TAA (guide T cells to tumor)
- Gene therapy - combines “tumor cell vaccines” with “cytokine therapy” by expressing genes coding for cytokines, costim. molecules or MHC
- Adaptive immunotherapy - antitumor cells (tumor infiltrating lymphocytes=TIL or lymphokine-activated killer cells=LAK)
Problems:
- Growing the large amount of cells required
- Loss of ag specificity for T cells
- Altering homing pattern
Causes of secondary immune deficiencies
- IV drug abuse
- Unsafe sexual activity
- Other risk behaviors
- Malnutrition
- Chronic diseases (e.g. diabetes)
- Medications (e.g. corticosteroids)
-> Development of AIDS or other secondary immue deficiency
Primary immune deficiencies
Genetic
- IgA deficiency
- CVI
- SCID
- other..
Leukocyte adhesion deficiency
Widespread pyogenic bacterial infections
Chronic granulomatous deficiency
- I.c. and e.c. infections
- granulomas
- decresed no. and function of phagocytes
- no NADH/NADPH oxidase in neutrophils -> less ROS
- decreased bactericidal activity
