10. Cancer Immunology Flashcards
3 components of tumour immunology
- immunosurveillance and immune status of patient
- cancer immunotherapy
- use of immunology to detect tumour markers
2 types of tumour markers/antigens
- tumour-specific
- tumour-associated
describe the experiment with inbred mice and tumour-specific transplantation antigens (4 steps) and the results
- brother-sister matings for 20 generations so mice are identical and can accept grafts
- tumour is injected and grows
- tumour is surgically removed and cut up into small pieces
- mice receives pieces of tumour
mice that originally had tumour was fine bc developed immune response to tumour –> TSTA
other mice die bc no immune response
why was Coley’s toxin created?
Coley saw that patients with erysipelas/bacterial skin infection had tumour regression
what is Coley’s toxin? and effect on tumour
mixture of attenuated bacteria that was injected into tumours –> saw some tumour regression but no cure
how do cancer vaccines work? (5 steps)
- remove tumour with surgery
- expose the patient’s own lymphocytes and/or DCs to their own tumour cells
- exposure stimulates lymphocytes/DCs
- reinfuse lymphocytes/DCs into patient
- some tumour regression
role of pro-inflammatory cytokines as cancer treatment
to expand naturally activated anti-cancer T cells
3 pro-inflammatory cytokines used in immunotherapy
- INFalpha
- TNF
- IL-2
results of pro-inflammatory cytokines as treatment IN VIVO
BAD SIDE EFFECTS
results of pro-inflammatory cytokines as treatment IN VITRO
expands anti-cancer T cells in vitro, then re-infuse into patient –> avoids side effect
describe:
1. normal T cell activation
2. checkpoint inhibition by CTLA4
3. CTLA4 inhibitor
- MHCII interacts with TCR and B7 interacts with CD28 to cause cytokine release for immune response
- CTLA4 blocks B7 interacting CD28 to prevent cytokine release
- CTLA4 inhibitor blocks CTLA4 so cytokines can be released
what is bispecific T cell engager?
2 half antibodies linked by short peptide to bring immune cell close to tumour cell
advantage and disadvantage of CAR-T cells
expensive but effective
what is PVS-RIPO?
modified poliovirus that can infect glioblastoma tumours, signaling the immune system to destroy the tumour
3 characteristics of tumour markers/antigens
- out of place
- out of whack
- out of time
why are tumour markers out of place?
- paraneoplastic syndromes –> hormones in wrong spot
- chromosomal translocation
why are tumour markers out of whack?
over-production –> M peak of multiple myeloma
what is the M peak of multiple myeloma and how does it tell us if therapy is working?
overproduction of monoclonal antibody –> if therapy works, peak will drop
why are tumour markers “out of time”?
oncofetal antigen –> CEA, AFP
8 applications of tumour markers
- detection
- diagnosis
- monitoring
- classification/prognosis
- staging
- pathology
- localization
- therapy
3 issues with early immunologic studies
- lack of adequate control tissue
- produced antitumour antisera by only 1 technique (antiserum absorption)
- few procedures could show tumour-specific antigens
why was it an issue that there was a lack of adequate control tissue?
could not differentiate tumour-specific antigens from patient-specific antigens
3 ways to fix the issues with early immunological studies
- obtain tumour and normal tissue from same patient to differentiate btwn tumour-specific and patient-specific antigens
- produce antitumour antisera by immunologic tolerance and immunologic absorption
- use multiple procedures to detect antitumour antibodies
4 procedures to detect antitumour antibodies
- immunoprecipitation in agar gel
- passive hemagglutination
- passive cutaneous anaphylaxis in mice
- IF labelling
describe the immunologic tolerance technique for production of antitumour antisera (3 steps)
- 8h after birth –> rabbit receives injection of normal bowel tissue from patient
- 3 months old –> injected with tumour tissue from same patient
- if tolerant to normal tissue –> should respond to tumour and give tumour-specific antiserum
describe the immunologic absorption technique for production of antitumour antisera (4 steps)
- inject tumour tissue into rabbit
- collect blood for anti-tumour antiserum
- add normal tissue extract
- gives tumour-specific antiserum
what was found in colon cancer extract?
had molecule not present in normal bowel tissue
describe the results of tissue analysis for looking at the tumour-specific antigen
significance?
- only cancers and metastasis from GIT, endoderm, liver, and pancreas were positive
- others were negative
therefore, the site of ORIGIN, not the site of growth, determines the expression of the tumour-specific antigen
why was the tumour-specific antigen called CEA?
CEA = carcinoembryonic antigen
found the same molecule in fetal and embryonic gut/pancreas/liver
where is CEA found in cell?
found ON membrane
distribution of CEA in normal vs tumour colon tissue
normal = only small amounts of CEA and only on villi
cancer = CEA found throughout
3 characteristics of CEA
- molecular mass = 180 kd
- carbohydrate side chains make up >50% of molecular mass with 28 possible N-linked glycosylation sites
- membrane anchored glycoprotein
how many epitopes are there are of CEA?
9
what structure does CEA resemble?
immunoglobulin
3 functions of CEA
- intercellular adhesion btwn integrins and fibronectins
- adhesion btwn bowel cell mucus and bacterial cell surfaces
- activity in stem cell maturation
how many CEA genes are there? how many are active, how many are pseudogenes?
what do most encode for?
29 CEA genes
18 active CEA genes
11 pseudogenes
most code for adhesion molecules with diff functions
what is the normal CEA level? what is it when there’s cancer?
normal CEA level = 2ng/ml
cancer CEA level >10ng/ml
why can you not screen for tumour markers?
bc they are also found in normal tissue
why is CEA tumour-associated not tumour-specific?
bc is it found in normal tissue
how can we test for CEA?
detect elevated and rising levels of CEA
what % of cancers have elevated and rising levels of CEA?
70%
3 reasons why detection of CEA is helpful
- monitoring
- staging
- prognosis
ASCO guidelines for colorectal cancer
- guide for staging, surgical planning, chemotherapy
- quarterly monitoring for 3 years for ppl with 2/3 stage of colorectal cancer who have had surgery/chemotherapy
- monitor response of metastatic disease to therapy
national comprehensive cancer network
- pre-operative CEA level is predictor of next disease-free interval
- decline of CEA post-op indicates the need for more chemo or surgery
