Cancer immunology-Hudig Flashcards
What is the immunotherapy for advanced melanoma?
adoptive transfer of tumor infiltrationg lymphocytes (TILs) CD8 CTLs
Why are TILs so awesome?!!?!?
because they affect only the tumor and it lasts a lifetime (immunological memory)
Why is not awesome about TILs?
immune response to tumor is limited because tumor is similiar to self (few antigens. tolerance)
What about a tumor makes it hard to be recognized as foreign?
low amount of antigen, lack of microbial ‘patterns’ to activate defenses, lack of inflammation at oncogenic site, immunosuppresion inside the tumor
What do microbial patterns activate?
APCs, generate IL-1, and TNF alpha cytokines and signal 2
What are the 2 types of immunotherapies?
passive
enhancing active immunity
Tumor immunity is (blank)
weak
Tumor antigens are tolerated as (blank)
self
Persistent immune responses to tumors leads to T cell (blank)
exhaustion
The tumor (blank) is suppressive
environment
Why is tumor immunity weak?
tumorgenesis induces T cell anergy- resulting in lack of inflammation and “signal 2”
Progression from normal to malignant is a multi-step mutational process that takes (blank)
years
Explain the path to get colorectal cancer
normal epithelium-> tumor supressor gene (APC) lost-> excessive epithelial proliferation-> oncogene (RAS) activated-> small benign tumor -> tumor suppressor gene (DCC) lost-> large tumor-> tumor becomes invasive-> rapid accumulation of mutations-> metastasis
The (blank) indirectly regulates transcription of a number of critical cell proliferation genes, through its interaction with the transcription factor beta catenin.
APC gene product
APC itself stabilizes
blank
microtubules
WHen unbound to netrin 1, (blank) activates apoptosis, so considred a “conditional tumor supressor”
DCC
In colorectal cancer, by regulating apoptosis in the absence in netrin-1, DCC is a conditional tumor suppressor. In normal conditions, DCC induced apoptosis limits cellular lifespan in the intestineal crypt and thereby inhibits the initiation of malignant transformation.
T or F
T
Absent (blank) expression is a strong predictor of poor survival in stage II and stage III CRCs
DCC
If p53 is autosomal what is the least number of mutational hits would it take to inactive p53.
2
T or F
very few tumors are caused by viruses
T (otherwise we could just go after the virus antigens)
Where are passive immunotherapies made?
fermenters
Where are active immunotherapies made?
CTLS in a person
If p53 is autosomal what is the least number of mutational hits would it take to inactivate p53
2 mutations
How many “hits” are illustrated here for colorectal carcinoma?
6 mutations and 1 oncogene (dominant)
What are the 3Es of tumor immunity?
Elimination; immunosurveillance of highly antigenic neoplasma
Equilibrium between tumor growth and immune killing
Escape; tumor loses antigens, secretes inhibitory factors, grows fast, recruits Tregs, etc…
When do you usually diagnose cancer?
after “escape”
want to re-create elimination or restore equilibrium
tumor is a (blank) arising from on cell
clone
What is the elimination phase of tumor immunity?
when tumor arise in tissue, a number of immune cells can recognize and eliminate them
What is the equilibrium phase of tumor immunity?
variant tumor cells arise that are more resistant to being killed
Over time a variety of different tumor varients develop
What is the escape phase of tumor immunity?
eventually, one variant may escape the killing mechanism or recruit regulatory cells to protect it, and so spread unchallenged
Transplantable tumors in syngeneic mice indicated (blank)
tumor immunity
Everyones tumor antigens will be (blank)
different
Research and recent clinical success have verified that some human tumors are recognized and can be killed by immunity… which ones?
melanoma, renal carcinoma, non-small lung carcinoma
Normal cells presents self peptides bound to MHC molecules. A poitn mutation in a self protein allows binding of a (blank) peptide to MHC molecules and creates a new (blank) for recognition by T cells
new
epitope
How can you get a tumor antigen?
by changing an amino acid in a self protein (middle of polypeptide binds to t cell receptor so 2 ways to make a tumor antigen) 1) point mutation in center of self peptide causes it to be recognized as foreign by T cell receptor 2) point mutation at end causing foreign recognition by MHC class I
What happens if you get a change in the amino acid of a self protein at the end of the 9-11 amino acid?
You will get a new peptide that will anchor into the MHC class I that is still seen as self to the T cell receptor but was not normally presented :) and is now seen as foreign cuz of the irregular attachment at the end
To get a CTL response, what other cells and antigens are needed?
T helper cells and MHC2 tumor peptide antigens and CTL
Where do you find tumor specific antigens (TSA)?
- on tumor cells but not on normal cells
- unique or shared (oncogenic viral ag’s)
What are some examples of TSA?
Ras mutant peptides in MHC 1;
Papilloma viral antigens in MHCI
What are tumor associated antigens (TAA)?
on tumor and normal cells
What are some examples of TAA?
melanoma MAGE
HER2 on breast carcinomas
Carinoembyronic antigen (CEA) on colon cancers, prostate specific antigens
(Blank) are products of mutated oncogenes and other tumor suppressor genes.
Tumor specific antigens
What are some tumor specific antigens?
- RAS mutations
- P210 product of Bcr/Abl (kinase)
- Mutated p53 tumor suppressor protein
- Viral antigens of EBV-associated tumors
- Unique Ig receptors on B cell lymphomas
(blank) mutations are in 10% of human carcinomas
Ras
(blank) rearrangements are common in chronic myelogenous leukemia (CML)
P210 product of Bcr/Abl
Mutated (blank) proteins are found in 50% of human tumors.
p53
(blank), (blank), (blank) in melanomas (normally expressed in melanocytes) are tumor associated antigens
tyrosinase, gp100, MART
(blank), (blank), (blank) proteisn expressed in melanoma and many other carcinomas, proteins that are normally only expressed in the testis and placenta. These are tumor associated antigens.
MAGE, BAGE, GAGE
(blank) are on some breast cancer cells. These are tumor associated antigens.
HER2
(blank) are higher on tumor cells. This is a tumor associated antigen.
Muc-1
(blank) factor and (blank) receptor are higher in cancer cells. This is a tumor associated antigen.
Epidermal growth factor (EGF) and EGFR
(blank) is an epithelial membrane antigen the is elevated in colon, breast, ovarian, lung and pancreatic cancers.
Muc-1 (mucin)
There are (blank) classes of tumor rejection antigens
7
What class of antigen do these belong to: Cycline-dependent kinase 4 Beta-catenin Caspase 8 Surface Ig/idiotype
TUmor-Specific
(mutated oncogene or tumor suppressor, unique to one cell, not in normal tissues_
What is the antigen that is found in melanoma and is a cell-cycle regultor?
cyclin-dpenedent kinase 4
What is the antigen that is found in melanoma and is a relay in signal transduction pathway?
beta-catenin
What is the antigen that is found in squamos cell carcinoma and is a regulator of apoptosis?
Caspase 8
What is the antigen that is found in lymphoma and is a specific antibody after gene rearrangements in B-cell clone
Surface Ig/idiotype
What class of antigen does this belong to:
Mage-1
Mage-3
NY-ESO-1
cancer-testis antigens
What antigen is this:
found in melanoma, breast, gilioma and are normal testicular proteins?
MAGE-1
Mage-3
Ny-ESO-1
What is the best class of antigen to develop drugs for?
tumor-specific
What class of antigen does tyrosinase and alpha fetoprotein belong to?
differentiation
What does tyrosinase and alpha fetoprotein do?
enzyme in pathway of melanin synthesis
What is the tumor type that tyrosinase and alpha fetoprotein are antigens for?
melanoma and hepatoma
What is the antigen and what class does it belong to: a receptor tyrosine kinase that is found on breast and ovary tumors
Her-2 neu (class is abnormal gene expression)
(blank) is a set of antigen-binding sites that characterizes the antibodies produced by a particular clone of antibody-producing cells.
idiotype
What is the most desirable tumor for anti tumor drugs?
melanoma
what is this antigen and what class of antigen does it belong to: works on leukemia and is a transcription factor;
wilm’s tumor-(class is abnormal gene expression
what is this antigen and what class of antigen does it belong to: works on breast and pancrease tumors, underglycosylated mucin
Muc-1 (class is abnormal post-translational modification)
what is this antigen and what class of antigen does it belong to: Works on melanoma, retention of introns in the mRNA
gP100 and TRP2 (abnormal post-transcriptional modification class)
What is the antigen and what class of antigen does it belong to: Viral transforming gene product that is found on cervical carcinoma and burkitt's lymphoma
HPV type 16. E6 and E7 proteins and EBV
There are 5 antigens found within melanom, this is why melanoma is most desirable tumor for anti-tumor immunity. t or f
t
What are the 5 cell types active in tumor immunity?
Th1 T Macrophages Cytotoxic T lymphocytes NK cells Tregs
How can you get TH1 T helper cells (CD4 ) cells to recognize a tumor?
the tumor needs to die to be presenting by MHC class II
DTH and TH1 activates (blank)
macrophages
Activated macrophages are (blank)
toxic/cytostatic
cytotoxic T lymphocytes kill tumors via tumor antigens in (blank) proteins
MHC1
What do this:
in immunosurveillance, to stress proteins
-late stage if tumors lose MHC class I’s
-active in ADCC if anti-tumor ab’s present
NK cells
What does this:
reduces CTL and NK function (baand THd)
Tregs
Tumors that lose (blank) expression can be killed by NK cells
MHC 1 expression
Are NK cells T cells?
no
(blank) are CD3-, use perforin and granzymes.
NK lymphocytes
What do NK and LAK (lymphokine-activated killer) cells do?
selectively kill virally infected cells and MHC I-negative cells
What makes up 15% of all peripheral blood lymphocytes (PBLs) in all people?
NK and LAK cells
How do Nk and LAK cells manage their killing?
have complex “on-off” receptors to “kill” and “inhibit killing”
Activating NK receptors such as NKG2 say (off/on) for killing
On
MHC i signals “off” through (blank) receptors on NK cells.
KIR
In the “on/off” balance of activation of NK and LAK cells, the balance usually favors (blank)
off
If you lose MHC I signals what happens to your killing balance?
NK cells stay on and kill
Control of NK cells is very well regulated. T or F
T
NK cells will not kill solid tumors, however if you activate them with (blank) you can activate them to kill.
IL-2 or IL-21
Tumor antigens take up and presented by APCs in absence of co-stimulation will be treated as (blank)
self
What are the five mechanisms where by tumors avoid immune recognition?
- low immunogenicity
- tumor treated as self antigen
- antigenic modulation
- tumor-induced immune suppression
- tumor-induced privileged site
What is antigenic modulation that can lead to avoidance of tumor recognition by immune system?
antibody against tumor cell-surface antigens can induce endocytosis and degredation of the antigen. Immune selection of antigen-loss variants.
How do you get tumor-induced immune suppression?
factors (ie TGF-beta, IL-10, IDO) secreted by tumor cells inhibit T cells and induce regulatory T cells (ie suppress immune response)
What are tumor-induced priveleged sites?
factors secreted by tumor cells create a physical barrier to immune system
The tumor microenvironment represents peristent antigens, what are they?
CTLA-4 down regulation of T cell division
Immune exhaustion of CTLs
(blank), also known as CD152 (cluster of differentiation 152), is a protein receptor that downregulates the immune system. It is found on the surface of T cells, which lead the cellular immune attack on antigens. The T cell attack can be turned on by stimulating the CD28 receptor on the T cell. The T cell attack can be turned off by stimulating the (blank) receptor, which acts as an “off” switch.
CTLA-4
CTLA-4
awesome anticancer target*
What are the types of immunotherapies?
- Passive mAb
- Enhancing active immunity
How do you get passive mAb?
blocking growth factor receptors
supporting ADCC
How do you get enhanced active immunity?
- increase weak anti-tumor immunity
- adoptive transfer of activated LAKs
- adoptive transfer of CTLs
- Vaccines to boost immunity
What is the monoclonal anti-HER2 for breast cancer ?
herceptin
What is the monoclonal anti-EGF for colon cancer?
Erbitux (cetuximab)
What is the monoclonal anti-CD20 for non-hodgkins lymphoma?
Rituxan (rituximab)
(blank) is the major effector mechanism for the major Mab’s for anti tumor associated antibodies.
ADCC
The alleles of CD16 which are F/F (used in ADCC) allow for more or less affinity with monoclonal therapies. If you have a F/F allele type rather than an F/O allele type, will you respond better or worse to rituxan
worse
what is the percent of F/F people in the general population?
32%
Her2, a receptor of EFG receptor family, is expressed on both normal tissue and 20-30% of all (blank)
breast carcinomas
What are the three breakthroughs of 2013?
- specific anti-tumor responses enhanced
- durable anti-tumor responses maintained
- responses persist without continual therapy
Anti-CTLA-4 (CD153) increases (blank)
tumor-specific T cells
Anti-programmed death receptor 1 (PD-1, CD279) to keep (blank) and (blank) alive and functional.
T helper
CTL
PD-1 receptor on T cell encounters PD-1 ligand and the (blank) dies
T cell
therefore you want to block PD-1
(blank) is co-stimulatory molecule with B7
CD28
What are the 2 Mabs to increase T cell activities?
Mab anti-CTLA-4 (CD 152)
Mab anti-PD-1 (CD279)
(blank) ipilimumab (YervoyR) IgG1 & tremelimumab IgG2; block one T cell checkpoint and support proliferation.
Mab anti-CTLA-4
(blank) nivolumab (?R) IgG4; pembrolizumab (KeytrudaR); lambrolizumab blocks programmed death receptor
Mab anti-PD-1
Which is better IgG1 or IgG4?
IgG4 because it does nto kill the cell (short half life)
igG1 has long half life
(blank) and (blank) block program cell death as a Mab anti-PD-1?
pembrolizumab
lambrozilumab
(blank) is an IgG1 and (blank) is an IgG2 blocks one T cell checkpoint and supports proliferation as a Mab anti-CTLA-4 (CD152).
Ipilimumab
tremelimumab
anit-melanoma, bladder, carcinoma, renal carcinoma, and nonsmall cell ung carcinoma responds to (blank) and (Blank) durably for greater than 2 years after 4 rounds of 2 mAbs every 3 weeks.
nivolumab
ipiimumab
What is a tumor vaccine?
to boosts patient’s active immunity.
Vaccine is autologous tumor transfected with genes for cytokines or other proteins.
What are the components of the tumor vaccine?
IL-2, gamma IFN, IL-12, TNFapha genes and B7 gene
What does the B7 gene do?
provides T cell costimulation
How do you make a tumor vaccine?
put genes into bacterial plasmid w/ strong promotor. Transfect individual patients tumor w/ plasmid and grow transfected autologous tumor and use as immunogen (good in mice, yet to work well in people)
Most tumor rejection antigens are unique to a specific (blank), so tumor vaccines may need to be customized for each patient.
cancer
To overcome (blank), individuals tumor can be transfected with B7 co-stimulatory molecules and used to re-stimulate T cells.
anergy
(blank) is the absence of the normal immune response to a particular antigen or allergen.
anergy
Malignant tumor cells expressing Tumor related antigens (TRA) but no co-stimulatory molecules. Naive CD8 T cells specific for TRA cannot be activated by the tumor cells and may be rendered (blank). If you transfect tumor cells with B7. Tumor cells expressing B7 can activate TRA-specific (blank) cells and activate them which can eliminate tumors.
anergic
CD8 T cells
tumors have (Blank) but most tumors are weakly immunogenic
tumor-specific antigens
Tumors evade immune detection and immune effectors. (blank) immunotherapies are in use against tumor associated antigens.
mAb
