Immun 1: Immunology

Question 1

How do T cells and B cells detect antigen?

Answer 1

T cells-TCR-AG on MHC presenting

B cells-BCR-membrane bound AB

Question 2

What is the cancer immunity cycle? Why can this cause issues

Answer 2

When cancer is present and growing -some will die, and release proteins, AG, etc
Captured by APC -presented to T cells etc
differentiate-CTL’s will infiltrate into the tumour-recognition of cancer and killed off the cancer cells (which releases more AG, repeating the cycle)

This causes a strong selection for cancer cells-so any that can evade that cycle have a incredible selective advantage

Question 3

What is immune checkpoint blockade?

Answer 3

Stopping the downregulatory elements of the cancer immunity cycle so that the immune system works better and kills more cancer

Question 4

How can tumours be detected by the body? What are the 2 elements that must be present to activate response?

Answer 4

As the cancer cell grows-will start producing inflammation as it goes through tissue (slow tho)
Leads to arrival of innate immune system and recognition of the threat -and then adaptive response

need: inflammation (danger signal) and antigen produced by cancer cell

Question 5

What are the issues in the bodies natural cancer detection?

Answer 5

The inflammation will come quite slow because cancer has to grow
Also the difference bewteen a healthy and cancer cell isnt massive-just a few mutations here and there-immune response cant always sense it

Question 6

How can T cells detect tumour specific antigen?

Answer 6

Similarly to virus infected cells -> all cells present peptide samples on MHC I /and some receptors -> recognisable by CTL’s as foreign/tumour AG

Question 7

What are tumour specific antigens?

Answer 7

Some AG are only found in AG-never found in healthy cells
Like viral proteins in cancer cells- epstein barr virus, HPV
Or some mutated cellular proteins-BCR-ABL, TGF-B receptor III - new AA sequence not found anywhere else

Question 8

in which kind of people do cancers of viral origin tend to develop initially?

Answer 8

usually opportunistic malignancies using immunosupressed people (EBV, HIV sarcoma) => will have viral proteins

But can also be with immunocompetent
HTLV1-leukemia
HepB/HepC-hepatocarcinoma
HPV-

Question 9

How does HPV cause cervical cancer? Solution?

Answer 9

Proteins from the HPV-E6 and E7 are oncogenes
=> disregulate the cell cycle -increasing it
E6/7 are intracellular antigens-and can/will be presented to the immune system

Capsule proteins are used to make a very effective vaccine-Gardasil 9

Most people actually give a strong response naturally (99%)-the vaccine is mostly for the 1% (and the vaccine can be given late-boost the immune system and it works)

Question 10

What are tumour associated antigen? Exemples?

Answer 10

NORMAL cellular proteins-but expressed in wrong place/wrong time/wrong amount
Because they are normal proteins-tolerance is an issue
Need to overcome that to generate normal response

Developmental AG-cancer testes AG (not normally in adult)
MAGE familty-Melanoma associated AG-(found in many different tumours) -internal
HER2-overexpressed in breast cancer
Mucin1-overexpressed in MANY cancer
Prostate-Prostate specific AG, prostate specific membrane AG, prostatic acid phosphatase

Question 11

How are T cells taught tolerance?

Answer 11

In thymus-gets rid of Autoreactive T cells in Thymus
Also ignore those that dont work well enough
But can fail-and everyone has a few T cells against self AG

Question 12

What are the 2 main problems for immunotherapy to treat cancer

Answer 12

Autoimmune response-limit that

Tolerance-normal tolerance to AG + cancer induced tolerance (if no library to enhance cant really work)

Question 13

How are Antibodies used to treat cancer? What are the main downsides?

Answer 13

Monoclonal AB-eg Trastuzumab - Anti-ER2/EGFR (breast cancer), CD20 (lymphomas) –naked AB
Conjugated-Radioactive particle taken to tumour-Anti-CD20 linked to yytrium90 (radioactive)
Anti-HER2 AB + cytotoxic drug (trastuzumab emtansine)
Bi-specific AB-genetically engineered to combine 2 specificities-anto CD3 and CD19-target B cell tumours

Costs a lot

LEARN SOME EXEMPLES–WHAT THEY TARGET

Question 14

What is therapeutic cancer vaccination?

Answer 14

Provenge-avdanced prostate cancer vaccine
patients WBC are treated by a protate fusion protein+cytokine => stimulated DC maturation and immune target of the protein-kills of the cancer

more of a US thing

Question 15

What is personalised tumour specific cancer vaccine?

Answer 15

every cancer and everyone will have different sequences-
can either take all DNA or RNA from the tumour cell-compare to the normal HLA from healthy cells
=> use that to indentify differences in AG-generate candidate vaccine to best suited AG in the tumour

has been used sucessfully in research but too time intensive (and expensive)

Question 16

What is immune checkpoint blockade?

Answer 16

Instead of boosting, try and remove the negative stimulation of the natural system
target CTLA-4 and PD1 pathways
use monoclonal AB to target these 2 proteins (CTLA-4 is on Treg, PD1 on activated Tcells)

Very general result-can be done for many people
Might cause autoimmune response
but has shown very good results

Question 17

What is adoptive transfer of cells for cancer therapy?

Answer 17

Take source of T cell (either blood or direct from tumour site)-expand them + stimulate them wil cytokines
Then re-infused into the patient –boost the cell number in the patient
can also engineer the Lymphocytes-Chimeric AG receptor- mix AB and TCR-create a AB that can target what we want and activate the cell-killem
(also the chimeric receptor can produce both signals needed for activation-immediate activation)
-> done by introduction of DNA in the cell

been used and worked
expensive