Immunotherapy Flashcards
What are the 2 inhibitor checkpoint molecules that are used for therapy?
PD-1 and CTLA-4
Explain the MOA of PD-1 and CTLA-4.
They suppress stimulation of T-cells.
They are both expressed on T cells and NK cells.
PD-1 is also expressed by myeloid cells and by certain tumours.
Do cancer cells expression MHC I or II?
- most tumours are generally MHC II negative.
- some are also MHC I negative to evade recognized by CD8+ cytotoxic T cells
What’s the MOA of myeloid derived suppressor cells?
the MDCS are recruited from the bone marrow normally by cytokines leased in inflammation. But can also be from the tumour.
Which are the major cytokines involved in the recruitment of MDSC during inflammation?
- granulocyte-macrophage colony stimulating factor
- IL-3
How does the tumour recruit MDSCs?
from multiple cytokines that are produced by tumours during hypoxia –> regulated by hypoxia inducible factor
What do the MDSCs do once they are in the tumour microenvironment?
- They differentiate into neutrophils and macrophages and actively suppress local anti-tumour response.
- potentiate Tregs
- differentiate into tumour associated macrophages
- They also produce metalloproteinases (MMPs)
How do tumour associated macrophage contribute to cancer progression?
it will stimulate tumour angiogenesis and promote metastasis
What’s produced by the MDSCs that can stimulate Tregs and differentiation of TAMs?
TGF-beta, and IL-10
What cytokine is involved in T cell activation?
IL-12, which is produced by TAMs to suppress T cell function
What else can lack of IL-12 and TGF-beta do in terms of immune suppression?
can cause NK anergy (lack of function)
What cell surface markers are expressed by Tregs?
CD4 and CD25
Which is the most specific marker for Tregs?
FoxP3, it’s an intracellular transcription factor
What are the actions of Tregs on the immune system?
can directly suppress CD4+ and CD8+ T cells, and NK cells
How does Tregs convert CD4+ cells to Tregs?
by locally produced IL-6, the TGF-beta
Which chemo drugs have shown to decrease Tregs?
cyclophosphamide
toceranib
What happens if there is an impairment of dendritic cell function?
less antigen presentation and stimulation of T cells –> T cell tolerance rather than activation
What are a few key immunosuppressive cytokines produced by the tumour cells?
- IL-10: Treg production and function
- VEGF
- TGF-beta: similar to IL-10; EMT
- TNF-alpha: induction of anti-apoptotic factors; promote angiogenesis and metastasis and hamper cytotoxic T cell and macrophage response
Which cytokines are related to anti-tumour immunity?
IL-12, IL-2, IL-3, IFN-gamma
How do MDSCs suppress T cells, NK cells, and dendritic cells?
Production of NO and ROS
What co-inhibitory surface molecules can tumour cells express to evade the immune system?
PD-L1/ CD73
What’s the outcome of liposome-encapsulated muramyl tripeptide for canine OSA, HSA, and MM?
OSA: no statistical difference in survival
HSA: better (DFI, and OS, 9m vs 5.7m)
MM: no statistical difference in DFI; but stage I had sig longer ST
What’s the response of Oncept IL-2 for FISS?
significantly longer mDFI (>730 days) compared to control group (287 days)
Can Oncept be used in cats?
yes, safe with minimal risks
What’s the outcome of canine cortical allograft for OSA that get infection versus not?
MST 685 days vs 289 days
Is there a difference in survival if there is infection at the site of OSA amputation site in dogs?
no
What are the functions of TAMs?
- IL-10 and TGF-β: increases & potentiates Tregs
- Produces NO, and reactive oxygen: Suppressed dendritic cells, NK cells, T cells
- MMP production: first step of metastatic cascade –> Angiogenesis
