Immune Checkpoints

Alessandra Curioni Fontecedro, MD

Departement of Oncology

University Hospital of Zurich

Activation of T cells requires two signals

Science 3 APRIL 2015 • VOL 348 ISSUE 6230

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

Co-inhibitory molecules: different activities

Eur. J. Immunol. 2015. 45: 1892–1905

CTLA-4, PD-1 Signaling

N Engl J Med 2012;366:2517-2519

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

Clinical trials acting on inhibitory molecules

Thank you for your attention