Tumor Immunology Flashcards
Tumor immunology is based on the preposition that tumors express _______________ that are not usually found on normal cells or they are expressed on normal cells at __________________ that they ___________.
novel antigens
such low levels that they do not provoke an immune response
What is immune surveillance?
the ability of the immune system to perceive respond to and control the growth and metastasis of neoplasms
What are the three stages of “immune editing”?
- elimination
- equilibrium
- escape
What two things could happen in the elimination phase?
it can lead to the complete eradication of the neoplasm or it can be incomplete and leave residual tumor cells behind that are dormant
What is “tumor dormancy”?
How does it occur?
If there is incomplete elimination of the neoplasm, the remaining tumor cells reach equilibrium where there is not detectable tumor growth.
What stage of immune editing experiences tumor dormancy?
Equilibrium stage and the tumor cells are killed as they are produced OR they just don’t grow
What is an “Escape Mutant”?
a tumor cell that no longer expresses tumor antigens so it is able to escape the immune system and proliferate
What elements of the innate immune response are involved in the elimination and equilibrium phases of immune editing?
Macrophages
NK cells
gammadelta T cells
What elements of the adaptive immune system are involved in the elimination and equilibrium phase of immune editing?
CD8 T cells
CD4 T cells
What cells do the immune escape phase involve?
CD4CD25 Tregs that suppress CD8 and NK cells
Genetically transmitted forms of cancer involve mutations in genes that control:
- cell growth
- DNA repair
- regulation of the cell cycle
What oncogene is involved in Burkitt’s lymphoma?
From what chromosome to what chromosome does it get translocated?
C- myc oncogene
From chromosome 8 to chromosome 14
What gene is c-myc translocated next to in Burkitt’s lymphoma?
What does this lead to?
next to the IgH gene of B-cells
This leads to uncontrolled B cell proliferation and tumorigenesis
What are three examples of chemical carcinogens?
asbestos, nitrate, nictotine/tar
What are two examples of physical carcinogens?
UV irradiation
gamma-irradiation
What are three examples of viruses that cause cancer?
- Epstein-Barr–> pharynx
- HPV–> cervix
- Human T cell lymphoma/leukemia virus (HTLV)
What are the 7 characteristics of cancer?
- Multistep process
- Heterogeneity –> malignancy
- Lack of antigens–> malignancy
- Lack of response to growth regulation–>malignancy
- Metastasis–> malignancy
- dormancy can be followed with relapse
- MDR–> malignancy
What are the 4 properties of tumor antigens?
- foreign or altered self (not expressed in thymus)
- high molecular weight
- chemically complex
- degradable with APC and can be located on MHCII
What are oncofetal antigens?
When are they present?
expressed during embryogenesis, but disappear in adult tissue and reappear on tumors
What are the two types of oncofetal antigens?
Carcinoembryonic Antigens (CEA) Alpha-fetaprotein (AFP)
What is CEA?
What types of cancer is it present in the serum for?
carcinoembryonic antigen- it is a oncofetal antigen that is expressed colon and pancreatic cancers and is present in serum
What is alpha-fetoprotein (AFP)?
What cancers is it present in?
An oncofetal antigen that increases in pregnancy , then dissipates
It increased with liver and pancreatic cancer
What are used as markers to detect tumor progression particularly for GI-related cancer?
AFP, CEA
What are the 5 major classes of tumor antigens?
- oncofetal antigens
- carbohydrate antigens
- clonal or differentiation antigens on lymphomas
- Mutant cellular gene products
- Viral gene products
What are the two types of carbohydrate antigens on tumors?
- gangliosides
2. mucins
What is a ganglioside?
What cancers is it expressed in?
glycolipids on normal neurons but overexpressed in melanoma and colon cancer
What is mucin?
What cancers is it expressed in?
under-glycosylated mucin does not require MHC presentation for T cell recognition and is expressed in breast cancer, ovarian cancer, and pancreatic cancer
What are B cell lymphomas?
monoclonal have Ab with the same idiotype which can be conjugated to a protein carrier and used as a vaccine
What mutant cellular gene products are expressed in tumors?
Growth factor receptors like EGFR, IL-2R
What type of carcinoma is Epstein Barr?
Nasopharyngeal
What two cells are involved in the innate response to tumors?
Macrophages and NK cells
What are the 5 ways a NK cell can induce cell death?
- Perforin-induced osmotic lysis
- TNF-a induced apoptosis
- IFN-gamma induced apoptosis
- Fasl-induced apoptosis
- ADCC
How do NK cells mediate tumor cell killing by ADCC?
NK cells express Fc receptors that engage the constant region of Ab that have coated the antigens on a tumor cell. When it binds, the NK cell releases perforin and the target cell dies
What two types of cancer are ADCC used to control?
Melanoma and lymphoma
What are the two types of macrophages?
M1- which is anti-tumor
M2- which is pro-tumor
When the macrophage releases IFN-gamma, what type of macrophage does it become?
Is it pro- or anti- tumor and what are the actions?
M1- anti-tumor
It releases TNFa, IL-12 (which stimulates Th1 which produces more IFN-gamma), and ROS
What cytokines differentiate macrophages to M2?
IL-4, IL-13, IL-10, glucocorticoids
What do M2 macrophages produce?
VEGF, MMP (matric metaboproteases which increase tumors invasive abilities) IL-10, Th2, arginase 10
What cells are involved in the adaptive immune response to tumors?
T-cells and B- cells
How do T cells respond to tumors?
- kill them directly by releasing perforin (CD8)
- Release IFN-gamma to activate NK cells and macrophages
- TNFa and IFNg to induce apoptosis OR initiate dormancy/senescence
How do B cells respond to tumors?
- produce antibodies that fix cancer cells or activate complement cascade
- Activate ADCC by engaging NK, basophils, eosinophils, macrophages
What is passive immunotherapy?
the person is transferred monoclonal antibodies against the tumor antigens
What are the five ways that passive immunotherapy antibodies can produce anti-tumor effects?
- direct complement lysis
- ADCC
- induce apoptosis
- inhibit angiogenesis
- blocking checkpoints that inhibit T-cell immune response
What are the four drugs that are FDA approved as passive immunotherapy against tumors?
What cancer does each treat?
- Rituxamib- B-cell lymphomas and chronic lymphocytic leukemia (CLL)
- Trastuzumab- Breast cancer
- Ipilimumab- melanoma
- Bevacizumab (avastin)- colorectal
How does Rituxamib block?
What kind of cancer does it treat?
What is the major mode of action?
It blocks CD20 on B cells and used to treat chronic lymphocytic leukemia (CLL).
It promotes ADCC
How does Trastuzumab work?
What type of cancer does it treat?
What are the modes of action?
It is directed against Her2 (human epidermal growth factor receptor) which is over-expressed in breast cancer.
It reduces proangiogenic factors and ADCC.
How does Avastin work (bevacizumab)?
What cancer is it used to treat?
What are the modes of action?
It is anti-VEGF and treats colorectal cancer prolonging lifespan by months.
It works by inhibiting angiogenesis.
How does Ipilimumab work?
What cancer is it used to treat?
What is the mode of action?
It is anti-CTLA4 so it blocks the molecule that deactivates T cells
(CTLA4 binds preferentially with B71-B72 so CD28 on the T cell can’t bind and thus signal 2 is not received by the T cell to activate)
It is used to treat melanoma but requires months/years to regress the cancer
Its mode of action is to block inhibitor receptors for T cell activation
What is the non-FDA approved passive immunotherapy drug in the works?
What is its mode of action?
What kind of cancer would it be used for?
Anti-PD-L1.
PD-L1 is expressed on a variety of normal tissues but is overexpressed on cancer cells.
PD-L1 binds to PD-1 on T-cells to shut off activation and inhibit inflammation by downregulating TNFa and IFNg
It is used for melanoma and kidney cancer
What is active immunotherapy?
Tumor antigens are combined with adjuvants (danger signals) to provoke immune response (inflammation)
What is adoptive cell transfer immunotherapy?
A patients cells from a tumor are removed and cultured in vitro to stimulate NK and macrophage response and antigen specific T cell response to “boost” the cells. They are then reinjected into the patient
Why is adoptive cell transfer immunotherapy considered an active and passive immunization hybrid?
It is sortof active because the patient’s own cells are generating the immune response (but in vitro instead of in vivo)
It is sort of passive because after the in vitro generation of boosted NK cells, macrophages, and antigen specific T cells, they are injected back.
What are two examples of adoptive cell transfer cells?
LAK- Lymphokine-activated Killer cell
Dendritic Cell vaccine (provenge)
What is a lymphokine-activated killer cell (LAK)?
What type of cell do they most resemble?
When they are injected back into patients, what do they direct?
What cancer are they used to treat?
Lymphocytes are collected from a patient and cultured in vitro with IL-2 to grow and generate these LAKs which are activated NK cells.
When injected back into the patient they direct cytolysis especially in melanoma.
What is Provenge?
What type of cancer is it used to treat?
dendritic cell vaccine–
- dendritic cells are cultured in vitro with GM-CSF and a tumor antigen
- they are adoptively transferred back to the patient where they present the tumor antigen to T-cells to generate specific T cell response.
This is used to treat prostate cancer.
What are the 4 major mechanisms utilized by tumors to subvert the immune system?
- reduce expression of tumor antigens on MHC1
- Elaborate anti-inflammatory/immunosuppressive factors
- Express cell membrane molecules to induce apoptosis of immune cells
- inactivate complement cascade
If the tumor downregulates antigen presentation in MHC1 molecules to CD8 cells, how might they still be killed?
By NK cells that lose their inhibitory signal (but still express their activating kill signal)
What are three tumor derived immunosuppressive molecules that control local response?
What two cell types are suppressed?
What soluble ligand controls immune response?
- TGFb, IL-10, Indoleamine dioxygenase (IDO) suppress local immune response
- Tregs and myeloid-derived supressor cells (MDSC) suppress NK and T cell mediated killing
3, Soluble FasL binds to Fas on T cells to induce apoptosis
What molecules do tumor cells express on their cell membrane to induce apoptosis of immune cells?
PD-1L to inhibit T cell proliferation and induce apoptosis
FasL to induce apoptosis
How do tumor cells inactivate the complement cascade?
Complementary Regulatory Proteins (CRPs) are secreted by tumors that inactivate the cascade and protect against lysis by complement fixing Ab.
