Tumour immunology Flashcards
How can tumours evade immune surveillence?
- They’re not immunogenic
- They arise from self cells
- Tumour cells can suppress immune function- TGFbeta
- Factors secreted by tumour cells can create a physical barrier
What is the innate immune system, and which cells are associated with it?
This type of defence is innate/ you’re born with it- its action does not depend on previous exposure to a pathogen
Cells: neutrophils, macrophages, natural killer cells
What is the adaptive immune system, and which cells are associate with it?
Slower more variable response, selective and specific to the pathogen
Cells: professional antigen presenting cells, B cells, T cells
What cell is predominant in the tumour microenvironment?
Macrophages
How can macrophages lead to tumour progression?
Factors secreted by macrophages:
TNFalpha and IL-6= enhance tumour cell growth
TGFbeta= enhances tumour cell tissue invasion
TNFalpha, IL-6 and TGFbeta= affect stromal cells and enhance metastasis
How can macrophages suppress tumour growth?
Factors secreted by macrophages:
IL-12= stimulates natural killer cells and cytotoxic t lymphocytes
Tumour growth is suppressed
Where are macrophages derived from?
Embryonic source, but more importantly- the bone marrow
What are TAMs?
Tumour-associated macrophages
found at tumour sites
chemotherapy can stimulate the production of tams
in breast cancer- 50-80% of the tumour can be TAMs
What are the types of TAMs?
M1= immunostimulatory pro-inflammatory tumoricidal perform ADCC (antibody dependent cellular cytotoxicity) are scarce M2= immunosupressive pro-angiogenic maintain t-regs do not perform ADCC predominant type of TAM
What was a recent discovery in immunotherapy history?
2015- oncolytic virus treatment
viruses can replicate in cancer cells but not in normal cells
What are the 5 main types of immunotherapy?
- Monoclonal antibodies
- Immune checkpoint inhibitors
- Cancer vaccines
- Adoptive cell transfer
- Cytokines
What is active immunotherapy?
Helps your host immunity becomes responsive to tumours
involves vaccination
What is passive immunotherapy?
The transfer of t. cells or antibody therapies
What are thy types of cancer vaccine?
- Killed tumour vaccine
- Purified tumour antigens
- Professional APC based vaccine
- Cytokine and costimulatory enhanced vaccines
- DNA vaccines
- Viral vectors
What is cell-based immunotherapy?
Therapy based on activating patients own immune system to attack cancer
cells used in this therapy: dendritic cells, t. cells and monocytes
Where are dendritic cells found, and what do they do?
Found under the epidermis- langerhan cells
the cells detect and engulf foreign invader cells and present a piece of the invader on their surface
How to make a dendritic cell vaccine?
Isolate white blood cells
enrich them to increase their population
lots of things activate a DC cell
What happens in T cell therapy?
Take a tumour biopsy cut the tumour into small pieces isolate T cells expand them in the lab put the T cells back into the patient T cells= killer cells
Why aren’t natural killer cells or stem cells as good as dendritic cells or T cells in therapy?
Cant expand them as well
Harder to isolate
What form of therapy is TIL?
Form of adoptive cell transfer - cells are grown and expanded from resected metastatic tumour deposits
What was the trojan horse treatment? What was the reason for it?
Trojan horse= macrophage
inside= cancer killing virus
Identified that hypoxic areas in tumour are a big issue- theyve changed their metabolism so they can starve but stay alive- are often resistant to chemotherapy and thus repopulate the tumour
TAMs accumulate in areas of hypoxia- if we can use TAMS as a vehicle- can reach the hypoxic areas
How does the trojan horse treatment work?
Take blood from patient
isolate monocytes (which readily turn into macrophages)
infect the monocytes with the virus
put the macrophages back into the patient
What are the problems associated with hypoxia?
Stimulates angiogenesis
suppresses the immune system
resistant to radio- and chemo-therapy
What was the initial experiment using the trojan horse technique- what happened?
Nude mice (with no adaptive immune system) were implanted with prostate tumour cells
they were then injected with the macrophage therapy
48 hours later- the prostate was removed and the tumour was analysed
By using prostate-specific GFP reporter- visualised the macrophages
Saw that out of the 3 million injected- only a small proportion reached the tumour
What was the result of combining the trojan horse treatment and chemotherapy (DOX)?
Shrank the tumours and kept them small
What needs to happen next for this treatment?
Move to clinical trials- be used on prostate cancer patients
expand the approach to look at other tumour types
improve the delivery of the therapy to tumours- currently- can only use this therapy for tumours you can reach
What is magnetic macrophage therapy?
Removing monocytes from a patient insert therapeutic virus load with ion particles put back the macrophages the macrophages will circulate in the blood, but by using a magnetic field, can be moved to the location of the tumour
How did magnetic macrophage therapy work with the trojan horse treatment?
Increased the traffic of macrophages to the tumour from 4% to 15%
What is MRT?
Magnetic resonance targeting
Used the magnetic field inherent to MRI to steer magnetised macrophages to the target site
MRI- locates the tumour, but then uses magnetic field (in pulses of 30mins/1 hour) to steer the macrophages
can increase the amount of macrophages reaching the tumour to 50%
