Lecture 13 (8A) - Host Response to Cancer Flashcards Preview

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Flashcards in Lecture 13 (8A) - Host Response to Cancer Deck (29):
1

There are 3 major causes of death in industrialized nations

• infectious disease (decreasing)
• cardiovascular disease (increasing)
• cancer/neoplasia (increasing)

2

Inverse relationship between

the incidence of prototypical infectious disease
and
the incidence of immune disorders
from 1950-2000

lower hepatitis A, tuberculosis, measles, rheumatic fever

higher crohn's disease, multiple sclerosis, type1 diabetes and asthma

3

Most common neoplasms

breast cell carcinoma
creast
prostate
sqamous-cel
lung
colorectal
urinary bladder
melanoma
uterine
kidney and renal pelvis

4

Carcinoma

cancer of the epithelium

5

Sarcoma

cancer of the connective tissue

6

Lymphoma

cancer of the lymphoid system

7

Leukaemia

cancer of the blood

8

Humans v animals

humans = 90% carcinoma
animals = mostly sarcomas

9

Incidence of cancer has

increased as life expectancy ha increased
• to pass on genes must survive infectious disease

10

Does the immune system fight tumors?

• some claim that the immune system only fights tumors that are caused by the action of viruses (eg HPV in cervical cancer)
however
• yes - there is good evidence that the immune system fights tumors

11

The immune system is capable of fighting tumors
• inject killed tumour cells

• you immunize mice with dead tumour cells
1. inject killed tumour cells

2 weeks later

2a. inject live tumor cells of the same type
3a. animal is tumour free

2b. inject live tumor cells of different type
3b. animal develops tumor

12

The immune system immuno-edits tumors

inject live tumour cells into a NORMAL animal
--> a few weeks later harvest the tumour
--> re-inject the tumour cells to a new NORMAL animal
--> tumour is not immunogenic, and is invisible to the immune system
• already won against the immune system = grows faster

inject live tumour cells into an IMMUNODEFICIENT animal
--> a few weeks later harvest the tumour
--> re-inject the tumour cells into a normal animal
--> the tumour is immunogenic and is attacked by the immune system
• hasn't had to avoid the immune system before

IMMUNOGENIC = seen by the immune system

13

Immunosurveillance

the ability of the immune cells to detect tumour cells

14

Immunogenicity

an immunogenic tumour is one that induces an immune response
- immunogenic - seen by the immune system

15

Immunoediting

the action of the immune system in shaping a tumour
• tumour cells that can escape being killed by the immune system have a selective advantage
• these tumours become progressive LESS immunogenic
• immunoescape = avoid the immune system
• immunoediting = tumour tries to stay ahead/avoid the immune system

16

Cytotoxic T cells can kill tumour cells

tumour cell displays tumour-associated antivens on MHC
MHC-I + tumour-antigen
(also dislays self-antigen)
• when tumour antigen is displayed on MHC-I cytotoxic T cells recognize and kill

would have self-peptides in groove, but with the tumour some proteins have been changed (new antigen) - cytotoxic T cell recognizes self-antigen that's been changed

17

Tumour antigens (TAs)

TAs are antigens that are presented (by MHC) to T cells
• these antigens are not normally seen by the immune system sot hey induce an immune response
• there are 6 types of these antigens

• TSA = mutationin a particular gene that's associated with the tumour (an oncogene)
• TAA = testis-specific antigens
• TAA = tissue-specific antigens
• TAA = strongly over-expressed antigens
• TSA = abnormal post-translational modifications
• TSA = viral proteins that cause cancer

TAA = tumour associated, found elsewhere
TSA = tumour specific, only in tumours

18

NK cells can kill tumour cells

in a normal cell, self-peptides are presented in MHC-I
• inhibitory receptor recognizes the side of the self MHC --> no killing

tumour antigens displayed in MHC --> run a risk of being recognized and killed by cytotoxic T cells
• so the tumour cell removes the MHC-I from the surface
• danger/stress ligands are displayed on the surface of the tumour cell
--> activating receptors of the NK cells recognize this and kill the tumour cell

19

What kills tumour cells?

• cytotoxic T cells
• NK cells
• γδ T cells
• INF-γ

20

The role of γδ cells in tumour immunosurveillance

• no γδ = more tumours than normal mouse
• no γδ or αβ = even more tumours

21

γδ T cells can kill tumour cells

• tumour cell displays MHC-I with both self-peptide and tumour antigens
• cytotoxic T cell recognizes the tumour antigen + MHC
• the tumour removes MHC-I + tumour antigen from the surface to keep from being recognized by the cytotoxic T cell

• NK cell recognizes self MHC so inhibits killing

• the tumour cell puts stress/danger signals on its surface
eg CD277 - sterss dimer flat on surface
• tumour makes pyrophosphate, makes IPP that binds inside DC277
--> CD277 changes from lying flat to sticking out
• the γδ T cell recognizes the CD277 with its γδTCR, and NKG2D recognizes the other stress ligands
--> tumour cell killed

22

IFNγ

• induces efficient MHC-I antigen processing and presentation by the tumour
+
• promotes a TH1 helper T cell response
=
promotes recognition and elimination of tumour by specific CD8+ T cells
• activates macrophages to kill tumour cells
• induces TRAIL
expression or NK cells (promotes tumour killing)
• indcuces the chemokines IP-10 and MIG which inhibit angiogenesis (starves the tumour)

23

How do tumours evade the immune system?

1. have low immunogenicity
2. by being perceived as self
3. by escaping the immune system due to mutation
4. by actively suppressing the immune system
5. by physically hiding from the immune system

24

Tumour evasion
• Low immnogenicity

MHC-1 no good one to present tumour antigen or MHC-I that presents it isnt present or is inside
• tumour antigens aren't displayed
• tumour antigens are displayed on MHC-I but MHC-I is removed from the cell surface

==> aren't recognized by cytotoxic T cells

25

Tumour evasion
• escape by mutation

• tumour cells are displayed (via MHC-I)
--> recognition by cytotoxic T cell and tumour attacked
• tumour mutates --> escapes action of cytotoxic T cells

26

Tumour evasion
• being seen as self due to lack of DC costimulation (little inflamation)

• tumour antigens are being taken up by immature DC
• DC displays the tumour antigen (via MHC-II) WITHOUT costimulation
- no B7 and no CD40
- naive CD4+ T cell -->
regulatory CD4+ T cell
== a T-reg is generated instead of an effector T cell
• the T-reg then protects the tumour by inhibiting the function of cytotoxic T cells

27

Tumour evasion
• active immune suppression

tumour produces immunosuppressive cytokines such as TGFβ
--> inhibits cytotoxic T cells and helper TH1 cell

28

Tumour evasion
• by physically hiding

tumour produces a barrier such as an extracellular matrix etc
--> cytotoxic T cell and helper TH1 cell blocked

29

Leukemia
• bone marrow transplant

• 50% die (graft virus-vs-host disease: bone marrow attacks the recipient)
• 25% die (leukemia returns)
• 25% survive (graft-vs-leukemia reaction - bone marrow attacks and eliminates the residual disease)