lecture 11 exam 2 Flashcards
tumor antigens
- excessive amounts of normal proteins - overproduction of normal cell products
- cancer/testis antigens - proteins of unknown function
- viral encoded proteins - products of genes of oncogenic viruses
- mutated proteins - altered forms of normal cellular proteins
- differentiation antigens - proteins associated w specific stages of cell differentiation
tumor localized inflammation promote tumor formation
inflammation -> NF-KB, STAT3 (trans factors) -> chemokines, cytokines and prostaglandins -> inflammatory cell recruitment -> cancer related inflammation -> cancer -> continues cycles
sarcoma from post vaccine on cats
homogenous malignancy
oncogenic virus -> malignant transformation -> identical new antigens
heterogenous malignancy
chemical carcinogen -> malignant transformation -> dissimilar new antigens
management of tumors
surgical removal of solid tumors treat w chemotherapy/radiation therapy immunotherapy: -antibody -CTLs -inhibit Tregs immunomodulation and vaccine development
how tumors escape immune defenses
antitumor immunity (kills tumor) immune evasion
antitumor immunity
tumor cell w MHC molecule presents tumor antigen to T cell specific for tumor antigen
t cell recognition of tumor antigen leading to T cell activation
immune evasion by tumors
failure to produce tumor antigen
-antigen loss variant of tumor cell - lack of T cell recognition of tumor
mutations in MHC genes or genes needed for antigen procesing
-class 1 MHC deficient tumor cell - lack of T cell recognition of tumor
production of immuno-suppressive proteins
-inhibitory ligan (PDL1 w immunosupressive cytokines (TGFB)) - inhibition of t cell activation
evasion of immune system by tumors
- loose expression of: tumor antigens (MHC1, TAP)
- secrete immunosuppressive cytokines: IL10, TGFB
- tumor cells present antigens in a tolerogenic form to mature lymphocytes - depressed or lack of costimulatory molecules
- tumor cells may induce anergy: Tregs - produce programmed death ligands that bind death receptors on T cells
- antigen masking: blocking antibodies - noncomplement activating antibody may bind and mask tumor antigens
major cell types & cytokines involved in tumor destruction
T cell + NK cell + macrophage
IFNgamma, IL2
IFNgamma (from NK to macrophage)
TNFa, IL12 (from macro to NK)
protective antitumor immune strategies
immune stimulants -> NK cells, activated macrophage, depressed regulatory cells
cytokines -> activated cytotoxic cells
immunotoxins
induction of t cell responses to tumors
tumor antigen in tumor cell -> ingested by host APC -> CD40 + CD40L binds to CD4+ thelper cell releasing cytokines to activate CD8+ which binds to APC that is phagocytosing tumor cell -> differentiation of tumor specific T cells -> tumor specific CD8+ CTL which will recognize tumor cell and killl!!
tumor vaccine
vaccinate w tumor antigen presenting DC (DC transfected w plasmid expressing tumor antigen + DC pulsed w tumor antigens) -> APC producing tumor antigen bind CD8+ Tcell which activates tumor specific T cells
enhancement of tumor cell immunogenicity
tumor cell transfected w gene for lymphocyte costimulator (IL2 or B7) -> vaccinate w tumor cell expressing costim or IL2 -> B7 expressing tumor cell stimulates tumor specific T cell + IL2 enhances proliferation & differentiation of tumor specific T cells -> activation of tumor specific T cells
adoptive transfer of tumor specific cells
tumor bearing patient, isolate lymphocytes from blood or tumor infiltrate -> expand lymphocytes by culture in IL2 -> transfer lymphocytes into patient w or wo systemic IL2 -> tumor regression as CTLs become specific w IL2
canine melanoma vaccine
treatment of dogs w stage 2/3 melanoma and for which local dz control has been achieved (negative local LNs or positive LNs were surgically removed or irradiated)
tyrosinase protein is overexpressed on melanoma cells and is the antigen target in vaccine
but tyrosinase is a self protein - xenogeneic DNA
xenogeneic DNA immunization strategy
canine tyrosinase antigen does not lead to immunity BUT human tyrosinase antigen in dogs leads to immunity bc no a self protein!
activation of antitumor innate immune responses
bacille calmette-guerin (BCG)
activates macrophages using TNFa, IL12, NO
theracys (live BCG): human melanomas, bladder tumors
regressin: cell wall extract for equine sarcoids
mechanical tissue damage: inflammation
a yearling w bovinepapilloma virus warts can be quished w hemostats -> this tissue exudate/DAMPs stimulates an immune response and it can be treated!
antitumor antibodies
antibodies to program death signals
tumor cells can inhibit the bodys immune response by binding to proteins such as PD1 on surface of T cells - antibody therapies block this binding in order to reactivate immune response
diagnostic tests
immunophenotyping by flow cytometry/IHC for tumor markers
cytologic evaluation of cells
molecular based assay (PCR) to determine mutations
products of oncogenes & tumor suppressor genes
human tumor antigen
Ras mutations, p210 product of Bcr/Abl rearrangements, overexpressed Her-2/neu
products of overexpressed genes
human tumor antigen
tyrosinase, gp100, MART in melanomas (normally expressed in melanocytes)
differentiation antigens normally present in tissue of origin
human tumor antigen
prostate specific antigen
markers of lymphocytes: CD10, CD20, Ig idiotypes on B cell
therapeutic antitumor antibody
antibody that is used therapeutically
her-2/neu
humanized mouse monoclonal antibody
breast cancer
CD20 (b cell marker)
humanized mouse monoclonal antibody
B cell lymphoma
CD10
humanized mouse monoclonal antibody & immunotoxin
B cell lymphoma, in routine use to purge bone marrow of residual tumor cells
CEA
humanized mouse monoclonal antibody
GI cancers, lung cancers
carcinoembryonic antigen
