Final Exam Flashcards
what are 2 pieces of evidence in support of the theory of immunosurveillance
- mice without immune system = more cancer
- humans immunosuppressed = more cancer
- TILS = positive prognosis markers
describe the three Es of immunosurveillence
1) elimination- cancer cells arise but eliminated by immune system, immunosurveillence
2) equilibrium
3) escape - clinically detectable tumor
describe one way in which a self antigen can become altered or foreign looking in a tumor
during a viral infection, a virus infects a self cell and self proteins/peptides altered or messed up because of mutation, translocation, oncogene activation, overexpression
how can an immune response to an acute infection be potentially useful in preventing the emergence of a tumor
acute infections result in immune responses to altered self peptides and immune responses are protective against some tumor antigens
-odds ratio/childhood infections
describe what happens during an acute infection
- self cell stressed and gets messed up
- altered self antigens during infection
- memory T cells remain in body
what are the two general approaches for immunotherapy treatments?
stimulate existing response and passive immunotherapy
limitations to immunotherapy
price, big protein or cell into tumor, old person or person with cancer for a long time has not well immune system
innate immune system
- fast, immediate
- less specific
- cells (macrophages, NK, dendritic)
adaptive immune system
- slower to start (3-5 days)
- very specific
- cells (T/B)
steps for a virus/bacteria infection
1) innate immune system recognizes infection
2) dendritic cells take samples of the viral/bacterial proteins
3) dendritic cell processes proteins into peptides and present peptides on its cell surface with MHC
4) dendritic cell “looks for” T cell that can recognize the foreign peptide
5) T cell that recognizes the peptide will proliferate and differentiate into killer T cell
6) T cell returns to infection and kills infected cells with peptide presented on MHC
cancer steps related to infection
1) maybe? the innate immune system recognizes tumor presence
2) dendritic cells (DC) take samples of tumor proteins (antigens)
3) DC processes proteins into peptides and present peptides on its cell surface with MHC
4) DC looks for T cells that can recognize tumor peptide
5) T cell that recognizes the peptide will proliferate and differentiate into killer T cell
6) T cell returns to tumor and kills cells with tumor peptide
How do T cells kill a tumor cell?
- release of cytotoxic granules from T cell into tumor cell (initiate extrinsic apoptosis)
- express Fas protein on T cells to induce extrinsic apoptosis
how does T cell recognize a different peptide/MHC?
each T cell that your body makes has a unique T cell receptor
different peptides T cell can recognize
foreign invader peptides, tumor peptides, healthy self peptides
why are healthy self peptides bad for a tumor to have
T cells that recognize healthy self peptides get destroyed
define immunosurveillance
immune system constantly patrols the body and eliminates tumor cells as they arise
evidence for immunosurveillance (related to just mouse)
strongly immunogenic tumor is rejected/destroyed/killed in WT mouse and strongly immunogenic tumors don’t develop in WT mouse
define immunogenic
if a tumor is immunogenic, it has foreign looking proteins that the immune system recognizes
what must tumors do to avoid immunosurveillance
make proteins that look foreign
antigen is what
peptide on MHC protein
a cancer cell is a self cell with
self proteins
how can a self antigen become altered or foreign
- mutation
- cancer germline genes
- oncogenic virus
- gene overexpresssion
mutation
change in an aa gets presented, looks foreign to T cell
cancer germline genes
we have genes that aren’t expressed as adults- that T cells don’t get trained against so can be tumor antigens
oncogenic virus
can insert a foreign gene
gene overexpression
protein isn’t mutated, several fold increase in expression, rare self reactive T cell is more likely to bump into its peptide
3 Es
1) elimination
2) equilibrium
3) escape
elimination
cancer cells arise but are slim by immune system, immunosurveillance
escape
clinically detectably tumor
how have cancer cells evolved strategies to avoid immune selective pressure?
1) antigen loss variance
2) stop making MHC protein
3) tumors can produce immunosuppressive cytokines
4) tumor associated macrophages inhibit T cells
5) tumor cells often outcompete T cells for nutrients
6) tumor cells can overepxress proteins on their surface that inhibit immune cells (PD-L1 and CTLA-4)
antigen loss variance
cancer cells have tumor antigens that T cells can recognize but if a cancer cell stops making the protein that the T cell is recognizing then the cancer cell can survive
stop making the MHC protein downside
NK cells can recognize and kill self cells without MHC
stop making the MHC protein
T cells can’t “see” peptide samples
example of stop making the MHC protein
if mutated Ras is a tumor antigen
how are acute infections involved in immunosurveillance
acute infects are correlated with protection against some types of cancer
acute infections result in immune responses to BLNK and immune responses are protective against some tumor antigens
altered self peptides
what can happen during a viral infection?
virus infects a self cell and self proteins/peptides can be altered or messed up (post translational modifications)
an immune response to altered self during an infection will…
persist as memory and then if the same altered self peptides pop up on a tumor, memory immune cells can eliminate the tumor cells
approaches to immunotherapy
stimulate the immune response and passive immunization
stimulate the immune response
assumes an existing immune response that needs to be boosted
passive immunization
- bypass the immune response to tumor antigens
- don’t need an immune response to tumor antigens
- drug uses the immune system
therapies that utilize some aspect of the immune system include
antibodies, bone marrow transplants, CAR T cells
standard therapies for cancer
chemo, radiation,(kill rapid replicating cells) surgery (not metastasis)
immunotherapy advantages
more specific, fewer side effects, better at killing, can deal with metastasis
what are the different types of immunotherapies
- checkpoint blockage
- tumor antigen virus
- adoptive T cell therapy
- provenge/sipuleucel T
checkpoint blockade therapies
proteins on dendritic cells and tumor cells that limit T cell function ($$)
goal of checkpoint blockade therapies
boost limited T cell responses
how checkpoint blockade works
- make antibodies specific to checkpoint proteins
- inject the antibody and block checkpoint protein
- T cell boosted and bypass checkpoint inhibition
examples of checkpoint blockade
CTLA4: blocks checkpoint during T cell and dendritic cell interactions
PD-L1: antibody blocks interaction between T cell and tumor cell
checkpoint and radiation
good
checkpoint and chemo
bad, suppress immune
tumor antigen vaccines
requires that cancer cells have protein that look foreign ($$), no clinical effective
adoptive T cell therapy
-labor intensive and patient specific
-after injection, T cells can kill tumor cells remaining in body
-expand T cells
$$$$$
goal of adoptive T cell therapy
T cells kill tumor cells before tumor cells have a chance to mutate
provenge/sipulecuel T other name
adoptive dendritic cell therapy/dendritic cell vaccine
provenge/sipulecuel T
-isolate blood, isolate monocytes (immune dendritic cells)
-dendrion company (mature the dendritic cells with GM-CSF, expose to PAP)
-reinject dendritic cells
-dendritic cell must find T cells that it can activate
$$$$$
therapies that utilize some aspect of immune system
antibodies, bone marrow transplants, CAR T
antibodies actual name
antibody dependent cellular cytotoxicity (ADCC)
ADCC
- design antibodies to bind to a tumor protein
- tumor gets coated
- NK cells kill antibody coated tumor cells
examples of antibody immunotherapy
Herceptin/trastuzumab and Rituximab
Herceptin/trastuzumab
- antibody binds HER2/new growth factor
- HER2/new expressed by breast epithelial cells/overexpressed on some breast cancers
mab
monoclonal antibody
Rituximab
- leukemia/lymphoma
- binds to CD20, expressed by B cells and over expressed on some leukemia/lymphoma
conjugated antibodies examples
- rituximab + radioisotope–> delivers radiation to cancer cells
- herceptin + chemo–> deliver chemo to cancer cells
benefits of conjugated antibodies
use lower doses of rad/chemo and localized drug delivery, less side effects
bone marrow transplant
- irradiate host/patient to kill their bone marrow cells, and cancer cells
- transfer done bone marrow (repop immune system)
CAR T cells
chimeric antigen receptor T cells, doesn’t require MHC or altered self but $$$$$$
CAR T cells advantage
could be any tumor protein, not just altered self or MHC and when CAR binds its target on tumor cell, signals to T cell to release cytotoxic granules
how does CAR T cell therapy work?
- isolate the cancer patient’s blood, isolate T cells
- transfer the chimeric antigen receptor gene
- expand T cells in a lab
- transfer T cells to patient
- severe symptoms from CAR T cells killing tumor cells
