Evidence for roles of MHC and T cells in tumor immunity
:
injected tumor cells may regress in immunocompetent mice but progress in T-cell deficient (irradiated) mice
experiment done using syngenic tumor grafts (allogenic tumors are automatically rejected)
conclusion: need intact immune system to affect a tumor rejection
inject irradiated tumor cells
Þ resistant to subsequent innoculation with same tumor
also resistant to other tumors of the same type if the two share immunologically important antigens
conclusion: tumor rejection is based on specific tumor antigens
immunity to tumors can be transferred via CD8 cells
tumor Ags and T-cell epitopes have been identified as well as T-cells specific for these Ags
immunization with tumor Ags (i.e. using dendritic cells as carriers) can illicit immunity
Þ
all these demonstrate memory and specificity in tumor immune response
Mechanisms of Tumor Immunity
humoral
T-cell: mostly CD8 cells via MHC I recognition; some CD4 via direct effector mech. or CD4 help
NK cells: very important especially in tumors that have reduced expression of MHC I
however, MHC and T-cells do not have a primary role in limiting tumors
evidence: nude mice, CD4ko, CD8ko, AIDS patients do not have an increased tumor incidence
exception: some rare cancers are more prevelent in AIDS patients (Kaposi’s sarcoma, some lymphomas)
origens of potential tumor rejection antigens
(1) embryonic (oncofetal)
antigens that were only expressed during deveopment; when immune system developed (post-nataly) these antigens were not around to be identifed as ‘self’; if they are produced in later life in a tumor, they are recognized as ‘foreign’
(2) abnormal post-translational modification
only Ag type to have been shown to be recognized by autologus T-cells in patients with breast or pancreatic tumors; post-translational events can make a protein seem foreign
(3) differentiation antigens
different from rest because these antigens are not truly foreign; they are expressed in some cells in the body, but when expressed in the wrong spot can illicit controlled autoimmunity
(4) mutated oncogene or tumor-suppressor (oncoproteins)
mutant ras and p53 are examples; these antigens promote the tumor, but at the same time provide a mechanism for immune recognition
(5) fusion protein
arise from abnormal gene rearrangement; similar to oncogenes
(6) oncoviral protein
virus-derived proteins are obviously foreign
How do tumors escape immune surveillance
?
low immunogenicity
: (main mechanism) no peptide-MHC ligand; no adhesion molecules; no co-stimulatory molecules
Þ
loss of MHC I decreases CD8 response, but increases NK response
without co-stimulatory molecules (i.e. B7), CD8 cells can recognize tumors but cannot be activated
antigenic modulation: i.e. antibody binding may induce endocytosis of the antigen or antigen modification
tumor-induced immune suppression: factors (TGF-b ) can be secreted by the tumor cell to inhibit T-cells
also, some tumors express Fas ligand Þ T-cell apoptosis if express Fas
Possibilities for Cancer Immunotherapy
Antibodies:
antibodies alone do not appear to be a good natural defense against cancer
current investigations are to conjugate a tumor-specific antibody to a toxin or radionuclide
the antibody is internalized by tumor cells and the conjugated toxin kills them
radiolabeled antibodies can be used to detect tumors (i.e. antibodies to carcinoembryonic antigen - CEA)
concentration of tumor antigens (i.e. CEA) in the serum can be used to follow progression or regression
Other Possibilites:
antibody/toxin conjugates
administration of leukocytes from patient that have been cytokine-activated and amplified in vitro