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bc4022 am > Lecture 5 > Flashcards

Lecture 5 Flashcards

1
Q

3 ways tumours suppress immunity

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

How do tumours create a suppressive metabolic environment?

A
  • 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
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3
Q

Tumour-associated ‘inflammation’ is similar to…

A

the wound-healing response

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4
Q

NF-κβ regulates expression of anti-apoptotic __

A

Bcl-2

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5
Q

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

A

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

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6
Q

NK cells patrol the body looking for cells that have…

A

lost expression of MHC Class I molecules

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7
Q

Inhibitory NK receptors contain __ in cytoplasmic tail

A

ITIMs (immunoreceptor tyrosine-based inhibitory motifs)

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8
Q

ITIMs engage with __

A

MHC Class I

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9
Q

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

A

DAP12
ITAMs

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10
Q

NK cells also express __ , which is responsible for ADCC

A

CD16 (low affinity IgG Fc receptor)

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11
Q

NK cells are activated by __ and produce __

A

Type I IFNs
IFN𝛾

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12
Q

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

A

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

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13
Q

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

A

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

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14
Q

What are neoantigens?

A

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

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15
Q

Examples of tumour-associated antigens

A
  • Cancer/testes antigens (MAGE, NY-ESO-1)
  • Oncofetal antigens (alpha-fetoprotein, CEA)
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16
Q

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

A

Sipuleucel-T (Provenge)
- licensed in 2010

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17
Q

Describe how DC-based therapies are made

A
  • Leukapheresis to enrich DCs; grow up with GM-CSF
  • Pulse with prostate antigen (prostatic acid phosphatase)
  • Reinfuse activated and Ag-loaded DC into patient
18
Q

True or False: Tumour cells are genetically unstable

A

True

19
Q

Different mechanisms tumour cells use to suppress T cell immunity

A
  • 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
20
Q

Treg cells are positive for…

A

CD4, CD25, FoxP3

21
Q

How do Tregs suppress the immune system?

A
  • 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)
22
Q

Low dose __ depletes Tregs

A

Cyclophosphamide

23
Q

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

A

Gemcitabine

24
Q

Cancer vaccine strategies that target MHC Class I

A
  • DNA (+/- electroporation)
  • Recombinant virus vector
  • Adjuvanted peptide-based personalised vaccines
  • DC loaded with Ag (e.g. Sipuleucel-T)
25
Q

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

A

Aldesleukin

26
Q

Anti-CD20 mAb used for lymphoma and leukaemia

A

Rituximab

27
Q

mAbs against CTLA-4

A

Ipilimumab, Tremelimumab

28
Q

__ is observed in cancer patients on immune checkpoint inhibitors

A

Autoimmunity (e.g. vitiligo)

29
Q

Ipilimumab was FDA approved in 2011 for the treatment of __

A

metastatic melanoma

30
Q

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

A

B7H1 (PD-L1)

31
Q

PD-L1 constitutively expressed on __

A

APCs

32
Q

PD1 inducibly expressed on…

A

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

33
Q

PD1 is upregulated on __

A

virus-specific CTLs

34
Q

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

A

T cell exhaustion

35
Q

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

A

True

36
Q

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

A

resistant to CTL lysis and Fas-induced apoptosis

37
Q

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

A

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

38
Q

How does PD1 expression affect the immune response?

A

It dampens down the immune response

39
Q

The two main mAb targets for T cell activation

A
  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
40
Q

Anti-PD1 monoclonal antibodies

A

Nivolumab, Pembrolizumab

41
Q

PD-L1 monoclonal antibodies

A

Atezolizumab, Durvalumab

42
Q

Radiotherapy can upregulate __ expression

A

MHC Class I

bc4022 am (8 decks)

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