Lecture 5

Question 1

3 ways tumours suppress immunity

Answer 1

1. Immunosuppressive cytokines (TGFβ, IL-10)
2. Inhibitory co-receptors (CTLA-4, PD1)
3. Suppressive metabolic environment

Question 2

How do tumours create a suppressive metabolic environment?

Answer 2

• IDO expression depletes tryptophan (supports Tregs)
• Tryptophan breakdown products (e.g. Kyn) may also block T cell activation & trigger T cell apoptosis, while also promoting the emergence of Tregs
• Tumour-associated macrophages support tumour cell proliferation & immunosuppression

Question 3

Tumour-associated ‘inflammation’ is similar to…

Answer 3

the wound-healing response

Question 4

NF-κβ regulates expression of anti-apoptotic __

Answer 4

Bcl-2

Question 5

How can chronic inflammation (e.g. chronic colitis or viral hepatitis) promote malignant transformation or tumour progression?

Answer 5

Activated macrophages & neutrophils can cause DNA damage through production of ROS & RNS (generation of mutations than can cause cellular transformation)

Question 6

NK cells patrol the body looking for cells that have…

Answer 6

lost expression of MHC Class I molecules

Question 7

Inhibitory NK receptors contain __ in cytoplasmic tail

Answer 7

ITIMs (immunoreceptor tyrosine-based inhibitory motifs)

Question 8

ITIMs engage with __

Answer 8

MHC Class I

Question 9

Activating NK receptors are associated with accessory proteins, such as __ , and possess __

Answer 9

DAP12
ITAMs

Question 10

NK cells also express __ , which is responsible for ADCC

Answer 10

CD16 (low affinity IgG Fc receptor)

Question 11

NK cells are activated by __ and produce __

Answer 11

Type I IFNs
IFN𝛾

Question 12

Effect of IFN𝛾 on (i) macrophages and (ii) DCs

Answer 12

(i) Stimulates IL-12 release from macrophages to enhance microbicidal killing
(ii) Enhances antigen presentation by DCs to T cells

Question 13

What response is absent in tumours that’s needed to fight cancer?

Answer 13

Type I IFN response (drives NK cell response, upregulates MHC Class I to induce CTL killing of tumour cells)

Question 14

What are neoantigens?

Answer 14

Tumour-specific antigens, mutated self-proteins or oncogenic viruses (e.g. EBV, HPV E6/E7 antigens)

Question 15

Examples of tumour-associated antigens

Answer 15

• Cancer/testes antigens (MAGE, NY-ESO-1)
• Oncofetal antigens (alpha-fetoprotein, CEA)

Question 16

Example of a DC-based therapy used to treat metastatic, asymptomatic, hormone-refractory prostate cancer (HRPC)

Answer 16

Sipuleucel-T (Provenge)
- licensed in 2010

Question 17

Describe how DC-based therapies are made

Answer 17

• Leukapheresis to enrich DCs; grow up with GM-CSF
• Pulse with prostate antigen (prostatic acid phosphatase)
• Reinfuse activated and Ag-loaded DC into patient

Question 18

True or False: Tumour cells are genetically unstable

Answer 18

True

Question 19

Different mechanisms tumour cells use to suppress T cell immunity

Answer 19

• Downregulation of MHC Class I (decreased Ag presentation to T cells)
• Loss of T cell epitope
• IL-10 stimulates induction of Tregs
• Kill Fas-positive T cells
• Tryptophan depletion (inhibits T cell proliferation)
• PD-L1 & PD-L2 (inhibit T cell activation)
• Downregulation of ICAM-1

Question 20

Treg cells are positive for…

Answer 20

CD4, CD25, FoxP3

Question 21

How do Tregs suppress the immune system?

Answer 21

• Inhibit Teff cells by CTLA-4, IL-10 & TGFβ
• Directly kill CD8+ CTL through granzyme & perforin (from the Treg)
• Metabolic disruption (IL-2 deprivation, cAMP transfer)
• Inhibition of DC function (Treg CTLA-4 binds B7 to induce IDO)

Question 22

Low dose __ depletes Tregs

Answer 22

Cyclophosphamide

Question 23

Myeloid-derived suppressor cells (immature DC, tolerogenic) can be depleted by __

Answer 23

Gemcitabine

Question 24

Cancer vaccine strategies that target MHC Class I

Answer 24

• DNA (+/- electroporation)
• Recombinant virus vector
• Adjuvanted peptide-based personalised vaccines
• DC loaded with Ag (e.g. Sipuleucel-T)

Question 25

Synthetic form of IL-2 for renal cell carcinoma and melanoma

Answer 25

Aldesleukin

Question 26

Anti-CD20 mAb used for lymphoma and leukaemia

Answer 26

Rituximab

Question 27

mAbs against CTLA-4

Answer 27

Ipilimumab, Tremelimumab

Question 28

__ is observed in cancer patients on immune checkpoint inhibitors

Answer 28

Autoimmunity (e.g. vitiligo)

Question 29

Ipilimumab was FDA approved in 2011 for the treatment of __

Answer 29

metastatic melanoma

Question 30

In chronic viral infections, __ is persistently expressed on both lymphoid and peripheral tissues

Answer 30

B7H1 (PD-L1)

Question 31

PD-L1 constitutively expressed on __

Answer 31

APCs

Question 32

PD1 inducibly expressed on...

Answer 32

ACTIVATED T cells, B cells, macrophages, DCs & monocytes (upregulation of PD1 on these cells has shown to inhibit both innate and adaptive immune responses)

Question 33

PD1 is upregulated on __

Answer 33

virus-specific CTLs

Question 34

The PD-L1/PD1 pathway has been identified to contribute to __

Answer 34

T cell exhaustion

Question 35

True or False: CTLs remain fully functional against PD-L1 negative tumours, but ignore PD-L1 positive tumours

Answer 35

True

Question 36

Upon PD1 ligation, tumour-associated PD-L1 acts as a receptor to deliver an anti-apoptotic signal to tumour cells, which renders these cells...

Answer 36

resistant to CTL lysis and Fas-induced apoptosis

Question 37

Effect of PD-L1/PD1 blockade by a PD-L1- or PD-1-specific mAb

Answer 37

Promotes CTL expansion and accelerates tumour regression or viral clearance in many murine tumour models or murine models of chronic viral infection

Question 38

How does PD1 expression affect the immune response?

Answer 38

It dampens down the immune response

Question 39

The two main mAb targets for T cell activation

Answer 39

1. Promote Ag-specific immune responses during priming in lymphoid organs (engage co-stimulatory pathways such as CD28 by agonistic reagents, or by blocking inhibitory signals e.g. CTLA-4 by an antagonist) 2. Expand effector T cells or restore exhausted T cells in peripheral organs (peripheral inhibitory pathways can be blocked e.g. PD-L1/PD1, or costimulatory receptors on Teff cells e.g. CD137 can be activated

Question 40

Anti-PD1 monoclonal antibodies

Answer 40

Nivolumab, Pembrolizumab

Question 41

PD-L1 monoclonal antibodies

Answer 41

Atezolizumab, Durvalumab

Question 42

Radiotherapy can upregulate __ expression

Answer 42

MHC Class I