ESMO Preceptorhsip on Immuno-Oncology Zurich...
Transcript of ESMO Preceptorhsip on Immuno-Oncology Zurich...
Immune Checkpoints
Alessandra Curioni Fontecedro, MD
Departement of Oncology
University Hospital of Zurich
Co-inhibition and co-stimulation determine the quality of the T cell response
NATURE REVIEWS CANCER VOLUME 12 APRIL 2012; 254
Co-stimulatory molecules, treatments in development
Name Function Treatment Company
CD28:CD80/86 T-cell activation and expansion
TAB08 TheraMAB
CD40:CD40L Maturation of dendritic cells
Activation/ differentiation of T-cells
IgG2 CD40-agonist Roche
OX40:OX40L Co-stimualtion of T cell activation
Suppression of Treg cells
MEDI0562 AstraZeneca
CD27:CD70 Maintenance of CD4 and CD8 T cell immunity
CDX-1127 Celldex Therapeutics
CD40/CD40L
maturation of dendritic cells activation/differentiation of T Cells
Nature Rev Immunol. 4:420 (2004)
OX40/OX40L
Nature Rev Immunol. 4:420 (2004)
Co-stimulation of effector T cells
Inhibition of regulatory T cells
CTLA4
On T regs: to aggregate around dendritic cells and inhibit their antigen-presenting activity
On T eff cells: as a negative feedback regulator
J Ex Med; 210(9), 1695–1710
The PD-L1 molecule
PD-L1 is expressed on: T cells, NK cells, macrophages, myeloid DCs, B cells, epithelial cells, vascular endothelial cells; tumor cells
Expression of PD-L1 is induced by : Type 1 and Type 2 IFNs, TNFα, LPS, GM-CSF, VEGF, IL-10, IL4
Expression of PD-L1 can be downregulated by: downregulation of PI3K; ALK/STAT3 ; NF-kB; miRNA513;wtPTEN
PD-L1 modulation of expression through hypoxia and IFN-gamma
Adapted from J Exp Med 2014;211:781-790
Hypoxia
IFNγ
PD-L1
• T cell death
• Down-regulation of activated T cells
• Reduction of T cells to kill tumor cells
The PD-L1/PD1 pathway leads to:
APC/ Tumor cells
T cell
Adapted from J. Immunology 2014, 193(8): 3835–3841
PD-L1 is important for Akt/
mTOR signaling in tumors.
PD-L1 enhances tumor cell
glycolysis and thus depletes
glucose from immune cells in
the tumor microenvironment
PD-L1 has also a direct tumor activity
Cell 2015; 162: 1229–1241
LAG3
LAG3 is upregulated • On exhausted T cells • On TIL • On T regs
Soluble LAG3 is an immunoadjuvant
LAG3 negatively regulates • T-cell activation • Proliferation • Homeostatic expansion
Adapted from Nature Reviews Immunology 15; 2015: 45-56