tumour immunology and immunotherapy of cancer

Question 1

what does PCD patient serum react with

Answer 1

CDR2 protein in tumour tissue (gives strong brown colour, showing antibody binding to tumour), so anti-CRD2 antibody present in serum

Question 2

significance of neurological symptoms in cancers

Answer 2

antibodies vs tumour have gone to brain and caused neurological disease in brain (autoimmune disease)

Question 3

what causes autoimmune diseases

Answer 3

spontaneous immune response against tumour-expressed antigen

Question 4

tumour immunity

Answer 4

immune response against tumour outside of blood-brain barrier

Question 5

autoimmune neurologic disease

Answer 5

immune response against CDR2 in neurones inside blood-brain barrier

Question 6

what causes PCD

Answer 6

elimination of Purkinje cells by tumour-induced auto-immune response (immune response against tumour antigen results in destruction of Purkinje cells in brain which normally express CDR2)

Question 7

what are Purkinje cells

Answer 7

type of motor neurone in cerebellum

Question 8

what can certain tumour express

Answer 8

antigens that are absent from corresponding normal tissues

Question 9

what does the immune system upon detection of abnormally expressed antigens by tumours, and consequence

Answer 9

launch immune attack against tumour, which could result in auto-immune destruction of normal somatic tissues

Question 10

2 direct evidences for immune control over tumours (immunosurveilance)

Answer 10

autopsies of accident victims show microscopic colonies of cancer cells with no symptoms of disease; organs donated by patients who have a history of cancer (melanoma) but were free of disease caused cancer in recipient (donors had “immunity” but recipients didn’t)

Question 11

2 indirect evidences for immune control over tumours (immunosurveilance)

Answer 11

deliberate immunosuppression (e.g. in transplantation) increases risk of malignancy; men have 2x greater chance of dying from malignant cancer than women (women typically mount stronger immune responses)

Question 12

describe immunosurveillance

Answer 12

malignant cells are generally controlled by action of immune system

Question 13

function of immunotherapy

Answer 13

attempt to enhance immune responses to cancer

Question 14

T cell receptor, and effects on molecules

Answer 14

aB, is “MHC restricted”

Question 15

B cell receptor, and effects on molecules

Answer 15

antibody, has effect on vast range of molecules (e.g. virus neutralisation)

Question 16

describe cancer-immunity cycle

Answer 16

release of cancer cell antigens (cell death) -> cancer antigen presentation (dendritic cells/APCs) -> priming and activation (APCs and T cells) -> trafficking of T cells to tumours (cytotoxic T cells) -> infiltration of T cells into tumours (tumour-infiltrating lymphocytes, cytotoxic T cells, endothelial cells) -> recognition of cancer cells by T cells (cytotoxic T cells, cancer cells) -> killing of cancer cells

Question 17

significance of immune selection pressure (disadvantage of immunotherapy)

Answer 17

any mutations or down-regulations can lead to advantages e.g. tumours lose ability to present MHC, so T cells can’t recognise so huge selection advantage, leading to outgrowth of cells that have down-regulated or have mutations in proteins required for antigen presentation)

Question 18

what can be targeted in cancer-immunity cycle in “immune checkpoint blockade”, and stages

Answer 18

programmed death ligands (PD-L”x”), in priming and activation and killing of cancer cells (remove negative regulators has same effect as increasing response)

Question 19

what does initiation of cancer (induction of mutations in cellular DNA) usually result from, and examples

Answer 19

multiple sporadic events over time e.g. irritation, chemical mutagens, spontaneous errors during DNA replication, tumour virus-induced changes in genome

Question 20

what causes tumour growth

Answer 20

aberrant regulation of apoptosis and cell cycle

Question 21

what does tumour growth eventually result in, and what does this cause

Answer 21

enough damage to release inflammatory signals, causing recruitment of innate immunity

Question 22

3 types of innate immunity cells which are initally recruited by inflammatory signals released by tumour growth

Answer 22

dendritic cell, macrophage, natural killer cell

Question 23

where do innate cells go to

Answer 23

drain into lymph node lymph node to activate adaptive immunity

Question 24

what happens after recruitment of innate immunity, and what cells does this involve

Answer 24

adaptive, antigen specific immunity (B and T cells), due to presentation of tumour antigens by dendritic cells and APCs

Question 25

2 requirements for activation of an adaptive anti-tumour immune response

Answer 25

local inflammation in tumour (danger signal) - innate, expression and recognition of tumour antigens - adaptive

Question 26

2 problems in immune surveillance of cancer

Answer 26

takes tumour a while to cause local inflammation, antigenic differences between normal and tumour cells can be very subtle (e.g. small number of point mutations)

Question 27

purpose of cancer immunotherapies

Answer 27

teach adaptive immune system to selectively detect and destroy tumour cells

Question 28

2 uses of cancer immunotherapies

Answer 28

alternative or supplement to conventional therapies (surgery, radiotherapy, chemotherapy)

Question 29

how do T cells recognise tumour-specific antigens

Answer 29

bind to MHC class I/II molecules, which display contents of cell for surveillance (infection, carcinogenesis); antibodies can also bind directly to surface for recognition

Question 30

what are tumour-specific antigens

Answer 30

antigens only found in tumour

Question 31

2 examples of viruses which display viral proteins that are tumour-specific antigens

Answer 31

Epstein Barr virus (EBV), human papillomavirus (HPV)

Question 32

2 examples of mutated normal cellular proteins displaying tumour-specific antigens

Answer 32

TGF-B receptor III (amino acid change due to mutation), Bcr-Abl (fusion of chromosomes generates new sequence of genes not found anywhere else)

Question 33

what are opportunistic malignancies

Answer 33

cancers of viral origin which occur when immunosuppressed

Question 34

2 examples of opportunistic malignancies, and cause of immunosuppression

Answer 34

EBV-positive lymphoma (post-transplant immunosuppression), HHV8-positive Kaposi sarcoma (HIV)

Question 35

3 examples of cancers of viral origin which exist in immunocompetent individuals

Answer 35

HTLV1-associated leukaemia/lymphoma, hepB virus- and hepC virus-associated hepatocellular carcinoma, human papilloma virus-positive genital tumours

Question 36

what induces and maintains cervical cancer due to HPV

Answer 36

IC antigens E6 and E7 oncoproteins of HPV

Question 37

what antigens are targeted for HPV vaccination

Answer 37

uses late gene surface proteins to make virus-like particles (for vaccine)

Question 38

consequence of cervical HPV infection and HPV-specific T cell immunity if strong immunity due to preventive (prophylactic) HPV vaccination (>99%)

Answer 38

clearance HPV-infection due to immunological memory

Question 39

consequence of cervical HPV infection and HPV-specific T cell immunity if immune failure as HPV vaccination has been unsuccessful (minority)

Answer 39

cervical neoplasia (50% no immunity, 50% non-functional immunity)

Question 40

if show early signs of disease, how can HPV vaccine be given

Answer 40

therapeutically