Lecture 13 (8A) - Host Response to Cancer Flashcards
There are 3 major causes of death in industrialized nations
- infectious disease (decreasing)
- cardiovascular disease (increasing)
- cancer/neoplasia (increasing)
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
Most common neoplasms
breast cell carcinoma creast prostate sqamous-cel lung colorectal urinary bladder melanoma uterine kidney and renal pelvis
Carcinoma
cancer of the epithelium
Sarcoma
cancer of the connective tissue
Lymphoma
cancer of the lymphoid system
Leukaemia
cancer of the blood
Humans v animals
humans = 90% carcinoma animals = mostly sarcomas
Incidence of cancer has
increased as life expectancy ha increased
• to pass on genes must survive infectious disease
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
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
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
Immunosurveillance
the ability of the immune cells to detect tumour cells
Immunogenicity
an immunogenic tumour is one that induces an immune response
- immunogenic - seen by the immune system
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
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
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
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
What kills tumour cells?
- cytotoxic T cells
- NK cells
- γδ T cells
- INF-γ
The role of γδ cells in tumour immunosurveillance
- no γδ = more tumours than normal mouse
* no γδ or αβ = even more tumours
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
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)
•
How do tumours evade the immune system?
- have low immunogenicity
- by being perceived as self
- by escaping the immune system due to mutation
- by actively suppressing the immune system
- by physically hiding from the immune system
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
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
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
Tumour evasion
• active immune suppression
tumour produces immunosuppressive cytokines such as TGFβ
–> inhibits cytotoxic T cells and helper TH1 cell
Tumour evasion
• by physically hiding
tumour produces a barrier such as an extracellular matrix etc
–> cytotoxic T cell and helper TH1 cell blocked
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)
