Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

MB4030 > Cancer > Flashcards

Cancer Flashcards

1
Q

How do cancers develop

A
  • consequence of genetic damage and mutations
  • loss of control of cell growth
  • failure of immune system to destroy malignant cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What causes cancer?

A

~80% due to environmental and lifestyle factors

20% due to genetic factors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Lymphoma

A
  • tumour in lymphoid tissue, bone marrow, lymph nodes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Leukemia

A
  • cancer of blood or bone marrow
  • abnormal increase in immature WBCs (‘blasts’)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Tumours

A
  • solid tumour masses
  • adenocarcinoma of colon, breast
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Immune response to tumours

A
  • Abs against tumour antigens can promote ADCC
  • CTL recognise TAA and triggers apoptosis
  • NK cells detect decreased/lack of MHC class I and triggers apoptosis
  • Macrophages cluster around tumour
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Macrophage types

A

M1
M2

  • dictates favourable correlation with tumour regression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is a favourable sign within a tumour?

A
  • lymphoid cell infiltrates
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Tumour antigens

A
  • expressed at high levels in some cancers
  • not normally expressed in tissue
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Types of tumour antigens

A
  1. Tumour Specific
  2. Tumour Associated
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

TSAs

A
  • ags expressed on tumour cells but NOT on normal
  • ags encoded by oncogenic viruses
  • oncofetal proteins - normally expressed in fetal development NOT in adult tissue, re-expressed in some cancers (CEA)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

TAAs

A
  • Ags expressed on normal cells but mutated/dysregulated/overexpressed in tumours
  • products of mutated genes e.g. mutated oncogenes (k-ras)/ TS genes (p53)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

K-ras

A

promotes gain of function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

p53

A

promotes loss of function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Nonsynonmymous mutations

A

random point mutations in protein-encoding genese can give rise to changes in AA sequence of the protein

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Mutanome

A

set of mutations that are very unique to an individual’s tumour

  • these mutated proteins differ from normal cellular proteins and can induce immune responses (abnormal peptode epitope antigens)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What type of environment does a tumour establish

A

immuno-suppressive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How does a tumour create an immunosuppressive environment?

A

Promotion of Anergy

  • **downreg of MHC I **-> failure of cancer cells to present cancer antigens
  • failure of APCs -> antigen not present efficiently to helper CD4+ and cytotoxic CD8+
  • failure of CD8+ -> dont engage and kill cancer cell by apoptosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Anergy

A

immunological tolerance characterised by the failure to mount a full immune response against the tumour

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What triggers immunosuppression

A

tumour, Tregs, M2 macrophages

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Areas of tumour

A
  1. parenchyma
  2. stroma
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Tumour parenchyma

A
  • made up of neoplastic cells
  • determines biological behaviour of tumour
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Tumour stroma

A
  • consists of BM, fibroblasts, ECM, immune cells, vasculature
  • provides support both growth and nutrition
  • promotes growth, invasion and metastasis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Solid tumours & TME

A
  • solid tumours use aerobic glycolysis (glucose to lactate)
  • immune evasion linked to metabolism and hypoxic conditions
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What do tumours secrete in TME

A
  • D-2HG metabolite
  • adenosine

*both suppress T cell activation

  • immunosuppressive cytokines (IL-10, TGF-B)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

3 sites of TME for therapeutic intervention

A
  1. Promoting Ag-presentation functions to DCs
  2. Promoting production of protective T-cell responses
  3. Overcoming immunosuppression in tumour bed
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Factors in cancer-immunity cycle
(release of cancer cell antigens)

A

Stimulatory
- immunogenic cell death

Inhibitory
- tolergenic cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Factors in cancer-immunity cycle
(cancer antigen presentation)

A

Stimulatory
- TNF-a
- IL-1
- IFN-a
- ATP
- HMGB1
- TLR

Inhibitory
- IL-10
- IL-4
- IL-13

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Factors in cancer-immunity cycle
(priming and activation)

A

Stimulatory
- IL-2
- IL-12

Inhbitory
- PD-L1/PD-1
- prostaglandins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Factors in cancer-immunity cycle
(trafficking of T cells to tumours)

A

Stimulatory
- CCL5
- CXCL9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Factors in cancer-immunity cycle
(infiltration of T cells into tumours)

A

Stimulatory
- selectins

Inhibitory
- VEGF
- endothelin B receptor

32
Q

Factors in cancer-immunity cycle
(recognition of cancer cells by T cells)

A

Stimulatory
- TCR

Inhibitory
- reduced MHC on cancer cells

33
Q

Factors in cancer-immunity cycle
(killing of cancer cells)

A

Stimulatory
- IFN-y
- T cell granules

Inhibitory
- PD-L1/PD-1
- Arginase
- TGF-B

34
Q

Tregs & Tumour Immunity

A
  • Tregs hinder effective anti-tumour immunity
  • Treg depletion effectively evoked anti-tumour immunity
35
Q

Foxp3

A
  • maj of cancers have Foxp3 effector cells
  • associated with poor prognosis
  • creates immunosuppressive environment
36
Q

Application of Treg depletion

A

Mabs

37
Q

Example of Mabs use in Treg depletion

A

CTLA-4

  • expressed by Teffs only upon activation
  • also Tregs in peripherary constitutively express CTLA-4

Anti-CTLA-4 MAb

= Ipilimumab

  • kills CTLA-4 expressing Tregs via ADCC
38
Q

Targets for Ab-mediated depletion of Tregs

A

CD25
CTLA-4

39
Q

What are macrophages

A

Tissue monocytes

40
Q

Types of macrophage

A

M1
M2

41
Q

M1 macrophage

A
  • proinflamm responses
  • LPS, TNF drives macrophage polarization to M1 phenotype
  • produce proinflamm cytokines (IL-6, IL-12)
42
Q

M2 macrophage

A
  • anti-inflamm responses
  • IL-4 drives macrophage polarization to M2 phenotype
  • produce anti-inflamm cytokines (IL-10, TGFB) chemokines (CCL17, CCL22)
43
Q

CCL17

A

attracts Tregs
*allows some cancers to evade immune response

44
Q

Early stages of infection

A
  • macrophages polarized to M1 fight against pathogen
  • later polarized to M2 anti-inflamm to help repair damaged tissued
45
Q

Can M2 macrophages be depleted?

A

via regulation of acidity, pH of lysosomes

ECM

46
Q

What drives macrophage depolarization?

A

low pH
hypoxia
ECM

47
Q

Alkaline agents

A

Chloroquine
- trapped in lysosome
- increase pH

Ca carbonate nanoparticles
- affect acidity by scavenging H+

48
Q

ECM remodelling

A
  • proteases and PIs - key regulators of ECM remodelling

Serpin E2
- overexpressed in cancers
- if inhibited - promotes M1 polarization - inhibits vascular invasion and spread of tumour

Mannosylated liposomes
- transform M2 to M1

49
Q

Stimulators of M1

A

LPS
PAMPs
TNF
IFNy

50
Q

Stimulators of M2

A

IL-4
MCSF
TGF-B
IL-13
IL-10

51
Q

3 distinct immune profules that correlate immunotherapy response

A
  1. immune-inflamed phenotypes
  2. immune-excluded phenotype
  3. immune-desert phenotype
52
Q

Immune inflammed phenotypes

A
  • **CD4 and CD8 T **cells present in tumour parenchyma
  • myeloid cells, monocytes in prox of tumour
  • contains inflamm cytokines that aid T cell activation (IL-2) (IL-12) (IL-23) (TNF-a)
53
Q

Immune excluded phenotype

A
  • immune cells present but they don’t penetrate tumour parenchyma
  • mainly in stroma
  • immunosuppressive environment
  • immune suppressive cytokines (IL-10, TGF-B)
  • promote tolerance
  • Tregs
54
Q

Immune desert phenotype

A
  • lack of of T cells in parenchyma or stroma
  • some myeloud cells
  • NO CD8 CTLs
55
Q

Non-inflammed tumours

A

immune-excluded and immune-desert phenotypes

56
Q

Possible factors that determine immune profile of a tumour

A
  • age
  • tumour genetic variation
  • microbiome
  • presence of infectious agents
57
Q

Cancer treatments prior to biologics

A

**Chemotherapy **
e.g Acute Lymphocytic Leukemia
- combo of prednisolone/dexamethasone, vincristine, asparaginase

**Radiotherapy **
- high energy Xrays to kill cancer cells and shrink tumours (external beam radiation)

58
Q

New Generation Treatments

A
  • Mabs to cancer specific Ags
  • Cytokines (IL-2, IFNs)
  • Immune checkpoint inhibitors
  • CAR-T cells
  • Cancer vaccines

*biologicals

59
Q

Post chemo treatment

A
  • GCSF & GMCSF (increase WBCs)
  • erythropoietin (increase RBCs)
60
Q

Therapies affecting cancer-immunity cycle

A
  1. Release of cancer cell antigens (chemotherapy, radiation, targeted)
  2. Cancer antigen presentation
    (vaccines, IFN-a, GM-CSF)
  3. Priming and activation
    (IL-2, IL-12, anti-CTLA4)
  4. Infiltration of T cells into tumours (anti-VEGF)
  5. Recognition of cancer cells by T cells (CARs)
  6. Killing of cancer cells (anti-PDL-1, anti-PD1)
61
Q

Mab example

A
  1. Rituximab
    - antigen: CD20
    - relapsed NHL
    - ADCC, apoptosis
  2. Trastuzumab
    - antigen: HER2/ErbB2
    - HER2+ breast cancer
    - receptor blockade, ADCC
62
Q

Kadcyla

A
  • Ab drug conjugate
  • consists of Herceptin Mab linked to cytotoxic agent (DM1)
  • tubulin inhibitor
  • Treatment for breast cancer
  • Triggers ADCC
63
Q

Immune checkpoint inhibitors

A

Immune checkpoints
- downregulate the response once infection is under control
- immune checkpoint receptors located on surface of Tcells and APCs - dampen response
- send off signals to APCs and Tcells

Immune checkpoint inhibitors
- block checkpoint proteins binding to partner proteins
- prevents off signal being transmitted
- T cells and APCs kill cancer cells

64
Q

Anergy in cancer

A

DC and CTL cells are unresponsive to cancer

  • CTLs and Th require activation
  • tumours trigger inhibitory signals
  • Mabs towards PD-1, PD-L1, CTLA4
65
Q

3 HPC vaccines

A
  1. Bivalent (Cervarix): 16,18
  2. Quadrivalent (Gardasil-4): 6,11,16,18
  3. Nonavlent (Gardasil-9): 6,11,16,18,31,33,45,52,58
66
Q

Neoantigens & Vaccines

A
  • effective anti-tumour immunity associated with T cells against cancer neoantigens
  • neoantigens are highly immunogenic
  • T cell pool specific for these neoantigens not affected by T cell tolerance
    i.e. neoanitgens absent during thymic education
  • patient specific
67
Q

How are neoantigens recognised?

A

Whole exome sequencing of tumour gene

68
Q

Desribe exome sequencing process

A
  1. Isolate genomic DNA from tumour
  2. Shear to small DNA fragments
  3. Use Gene arrays that contain all human genome exon probes to capture all exons in tumour cells
  4. This should contain the exon DNA sequences from the genes in the tumour
69
Q

Explain the process after cancer vaccine is administered

A
  1. DC uptake tumour antigens
  2. Present them to MHC I/II
  3. Antigen-loaded DCs migrate to LNs -> recruite and activate immune cells
  4. fDCs promote memory B cell and plasma cell generation
  5. Activated T cells - differentiate into memory T cells & effector T cells
  6. Teffs travel to TME - kill tumour directly or via apoptosis
70
Q

Application of personal. multi-peptode neoantigen vaccine

A

High risk melanoma

71
Q

Requirements of high quality neoantigens

A
  1. strong binding affinity for MHC
  2. expressed by most tumour cells
  3. generated via consequences of mutations that affect cancer cell survival

-> should induce robust immune response and prevent development of tumour-immune escape

72
Q

Example of vaccine

A

GNOS-PV02
(40 neoantigens for HCC treatment)

73
Q

Challenges to producing good neoantigens

A
  • small % of NAs generate
    strong immune response
  • different MHC alleles have** peptide structure requirements** for binding
    *MHC II bind larger peptides
    *A need for better MHC II peptide binding algorithms
  • T cell recognition of cancer assoicated Ags crucial for functional immune response to tumour
    *recognition of neoantigens by T cells is inefficient
    *10% non-synonymous point mutations generated peptides that bind to MHC I
    *fraction of these are highly immunogenic
  • identify highly immunogenic neoantigens
    *more immunogenic, better seen by T cells
74
Q

What makes NA vaccines a promising platform

A
  1. induces strong MHC I mediated CD8+ T cell response
  2. simultaneously deliver multiple antigens
  3. encode full length tumour antigens - allows APC to cross present various epitopes, present several antigens simultaneously
  4. simple and fast (at making long peptides)
75
Q

Examples of cytokine therapy

A
  • IFN-a2 (malignant melanoma)
  • immunostim cytokines w/ anticancer properties (IL-2, TNFa)
  • stimulators of haemopoiesis
    (GM-CSF, EPO)
  • immunosupp cytokines for RA, psoriasis, IBD
    (IL-4, IL-10)

MB4030 (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions