Lecture 8: Cytokines and Cancer Flashcards
Stromal cells
Any cells around the tumor
Tumor infiltrating lymphocytes (TIL) role in cancer
strongly correlated with survival in several cancer types
the more TIL, the higher the survival
3 cytokine functions
- Endocrine action (circulation to distant cells)
- Paracrine action (nearby cells)
- Autocrine action (stimulate itself)
4 properties of cytokines
- Pleiotropic (multiple effects)
- Redundant
- Synergistic
- Antagonistic
Cytokines cascade
activation of one cytokine produced by one cell type induce cytokine production by other cell types
Structure of cytokine receptors
consist of one or more transmembrane protein
extracellular: cytokine binding
cytoplasmic: initiation of intracellular signalling pathways
4 types of cytokine receptors
Type 1
Type 2
TNF receptor family
IL-1/TLR family
Cytokine receptor family function
must be dimerized
form reception complex with ligand
lack intrinsic kinase activity but associate with intracellular kinase
Innate immunity
first line of defense against infection
granulocytes, mast cells, macrophages, dendritic cells and natural killer cells
Adaptive immunity
mediated by antibodies and CD4 and CD8 T cells
Perforin and IFN-y double knockout mices
susceptible to spontaneous lymphomas
Compromised FAS-FAS ligand mices and function of FAS
FAS (TNF family receptor) (death receptor) helps to maintain B-cell and T-cell homeostasis
frequently form B-cell lymphomas
Rag2/Stat1 double knockout mice
regularly develop adenocarcinomas of the colon, breast and lung
GM-Csf/ IFN-y knockout mice
develop diverse blood and solid cancers with chronic infection
Cytokine therapies and the associated adverse effect
Systemic administration
stimulate anticancer responses
can lead to CYTOKINE STORM
IFN-a
induce NK cells and DC against tumor cells to inhibit cell proliferation and kill cancer cells
IL-1a
cytotoxic-cytostatic activity against refractory malignancies and solid tumor cells
IL-2
anticancer against hematologic malignancies (leukemia and lymphoma) in vitro, in vivo and clinical studies
IL-7
combination with human T-cells showed significant anticancer activity in human colon carcinoma via activation of the PI3K/AKT pathway
Mechanism of immune evasion
- loss of antigenicity
- loss of immunogenicity
- immunosuppressive microenvironment
CTLA-4
expressed by activated T cells and DC
inhibit signals to T cells
can be targeted by monoclonal antibodies to activate immune system
PD-L1 and PD-1
found on activated T cells
inhibits activation of IL-2 production and T cells proliferation
target and inhibit PD-1 receptor to reduce cancer evasion
Tumor infiltrating lymphocytes (TIL) therapy
remove TIL from patients
cultured with IL-2 to induce proliferation
infused back to patient and help immune system to kill cancer
performed in advanced (cutaneous) melanoma
antitumor activity in other solid tumor still remains a challenge
Car T-cells therapy
T cells collected from patient
insert gene to help locate antigens or proteins on the surface of cancer cells
infused back and allow T-cells to target and destroy cancer cells
T-cell receptor therapy (TCR)
T cells collected from blood
gene inserted to find specific cancer antigen or protein
infused back to patient to launch attack against cancer
In vitro sensitized (IVS) T-cell therapy
T-cells collected from blood
taught to recognize cancer cells through ex vivo activation (no genetic change)
multiplied and returned through infusion
Cytokine release syndrome
when tumor is destroyed, its releases large quantities of cell signalling protein molecules
the effect killed at least seven patients
