Lecture 21: Cancer Immunology Flashcards
what cell types never enter G0 phase of cell cycle
skin & hair follicles
GI epithelium
bone marrow
male gametes
_______ regulate the normal progression of the cell cycle
Checkpoints
Cancer occurs when ______ accure in the DNA of cells. resulting in the progression of the cell cycle without regulation at checkpoints
Mutations
what are the 2 classes of genes in which mutations result in deregulation of the cell cycle
Tumor Suppressor Genes (the brakes)
(Proto) Oncogenes (accelerator)
what are tumor suppressor genes
genes that produce proteins that inhibit progression through the cell cycle
- includes SNA repair enzymes and signaling proteins that block the cell cycle
- most common causes of cancer
what type of mutations do tumor suppressor genes cause?
recessive mutations
- both copies of the gene have to be inactivated
what are (proto) oncogenes
genes that produce proteins that promote progression through the cell cycle
mutations cause constitutive activation of signaling proteins in growth pathways
driver mutation
what type of mutations do proto oncogenes cause
dominant
- only one copy of the gene has to be activated
- cancer viruses like FeLV cause these kinds of mutations
what are passenger mutations
mutations that don’t deregulate the cell cycle
- instead, they endow cancer cell w/ other physiological changes that give them growth advantages (ex: cells that can survive in hypoxic conditions)
- can be caused by continued exposure to carcinogens or radiation or arise spontaneously due to defective DNA repair enzymes
what are tumor antigens
DNA mutations in cancer cells produce proteins that the immune system might recognize as foreign
the accumulation of mutations progressively increases the _______ of cancer cells
Antigenicity
- more mutations = more likely to be flagged by the immune system
what are tumor-specific antigens (TSA’s) or mutation-associated neoantigens (MANA’s)
unique to tumor cells
result from mutations in the exons of any gene or incorporation of oncogenic viruses
normal proteins that are inappropriately expressed by tumors
Tumor-associated antigens
what causes tumor associated antigens to form
mutations in gene regulatory elements
antigen that may be an overexpression of a protein or an expression of an embryonic or other immune privileged protein
tumor-associated antigen
explain immune surveillance
the capacity of the immune system to recognize and destroy transformed cells before they grow into tumors and to kill tumors after they are formed
- involved innate and adaptive immune responses
how do antibodies promote tumor cell destruction?
- enhancing innate immunity
- serving as opsonins
- activating complement and ADCC
cells capable of destroying tumor cells in a non-MHC restricted fasion. Are the first line of defense against many tumors
Natural Killer cells
cells that are effective against tumors with reduced levels of class I MHC
NK cells
what cells are strongly activated by INF-y and kill tumors by secreting TNF and ROS
Macrophages
- process and present tumor antigens to T cells
what is the most important immune mechanism for fighting tumors
tumor-specific Cytotoxic T-cells
- directed against tumor antigens presented by class I MHC molecules
what are the mechanisms for tumor elimination?
- tumor antigens get picked up by dendritic cells at the tumor site
- Cytotoxic T cells are activated in secondary lymphatics
- tumor-specific CTLs migrate back to the site and kill the tumor cells
what makes NK cells also critical in the killing of tumor cells
they recognize when MHC class I expression decreases…. which occurs in immunosuppressive tumor environments
what is ADCC
Antibody dependent cell-mediated cytotoxicity
immunoediting describes how ….
cancer cells respond to the immune system
the killing of cancer cells by NKs and CTLs selects for cancer cells with…
Fewer MHC class I molecules
Fewer MANAs
initial cancer cells are _______
immunogenic
immune cell killing is a _____________ that results in the survival and growth of tumor cells with reduced ________
selective pressure
reduced immunogenicity
most cancer cells have more ______ mutations than _____ mutations
more Passenger mutations than driver mutations
Cancer cell-associated mechanisms of immune escape (4)
- Decreased MHC expression (reduces recognition by CTLs)
- Decreased expression of costimulatory molecules (causes CTL anergy and induces tolerance)
- expression of T-cell inhibitory receptors
- Normal immune attenuation
what is the role of PD-L1 (ligand) in the expression of T cell inhibitory receptors
PD-L1 is a ligand for T cell receptor PD-1
- it increases CTL apoptosis
- decreases Treg apoptosis
what is CTLA-4
homolog of CD28 that inhibits CTL function
what cytokines do tumors secrete that activate repressive cell types
IL-4
IL-6
IL-10
TGF-B
MCF
PGE2
etc
Myeloid-Derived Suppressor Cells (MDSCs) express _____ to inactivate CTLs
PD-L1
what type of macrophages promote blood vessel formation and tissue repair
M2-polarized macrophages
what cells secrete IL-10 and TGF-B, induces apoptosis of CD8 and CD4 T-cells, reduces available IL-2 by binding to CD25
Regulatory T cells
what are myeloid derived suppressor cells
pre-myelocytes
what is Piroxicam used for
treatment of transitional cell carcinoma in dogs
bladder cancer.think P for pee, bladder
what kind of drug is Piroxicam
non specific cyclooxygenase (COX) inhibitor
how does Piroxicam work
induced tumor cell apoptosis
- possibly by reducing angiogenesis
what is Mycobacterial Cell Wall Fraction Immunomodulator used to treat
Dogs - Mixed Mammary tumors and mammary adenocarcinomas
Horses - sarcoids, equine respiratory disease, metritis caused by Streptococcus zooepidemicus
what is the mechanism of Mycobacterial Cell Wall Fraction Immunomodulator?
local injection promotes inflammation
- oil in water emulsions of cell wall fractions
- indicated M1 macrophage activation and stimulates IL-1 release
Glucocorticoid treatment for Lymphoma
prednisone/prednisolone
used as one of the drugs in the CHOP method
how does prednisone work
induces apoptosis of most lymphocyte classes
uses of prednisone
lymphoma & in non-CHOP protocols for treatment of multiple myeloma
Guanine nucleotide analog treatment for lymphoma
Rabacfosadine (Tanovea CA-1)
- A pro drug that has to be metabolized into the active form
- active form gets incorporated in DNA chain of replicating cells
How does Rabacfosadine work
doesn’t have a ribose base that DNA polymerase recognizes
terminates the replication of DNA chains during S phase of cell cycle
RabacfoSadine
Drug used as part of the RESCUE protocol when remission of lymphoma in dogs can’t be achieved w/ CHOP
Asparaginase (Elspar)
how does Asparaginase work
- enzyme that degrades circulating asparagine
- deprives lymphoid cancer of a necessary amino aicd
- causes lethal metabolic stress
What is Toceranic (Palladia)
a competitive antagonist of ATP binding to the kinase domain of c-kit
what is c-kit
an oncogene mutated in 25-50% of all canine mast cell tumors
how does mutant c-kit work
- signals continuously in the absence of its ligand (constitutive activation)
- causes unregulated cell proliferation of leukocytes, esp mast cells (driver mutation)
what is the goal of anticancer vaccines?
they deliver antigens that induce an adaptive immune response and creation of memory T cells
examples of specific anticancer vaccines
Feline Leukemia Virus
Canine melanoma (Oncept)
Canine B cell lymphoma
Marek’s Disease in Chickens
_____ mutations occur in oncogenes or tumor suppressor genes and cause unregulated progression through the cell cycel
Driver
_______ mutations may give cancer cells new activities but do not cause the disease
Passenger
antigens that arise from mutations can be tumor _____ or tumor ______
tumor-specific or tumor-associated
immunoediting selects for cells that are resistant to …
the immune system
cancer treatments that alter immune system function in non-immune system cancers include…
Piroxicam and mycobacterial cell wall immunomodulatory
cancer treatments for cancers of the immune system include…
prednisone
rabacfosadine
toceranib
asparaginase
vaccines
