Page 13 - linda_borst

A A B B
m
u
d
m
r
o
o
m
y
L Lymph node e T Tumor microenvironment t
n
h
p
o
r
i
n
n
e
m
r
c
i
o
v
n
e
l
o
h
e
T T cell l E Effector phase
c
f
e
p
e
r
t
s
f
a
c
t
a activation n
c
i
i
o
t
v
a
T cell
APC Activation &
expansion
Cancer cell
Priming signals Immune attack
B7 CD28 TCR MHC
Chapter 1
MHC TCR CTLA-4 B7
PD-1 PD-L1
TIM3 Galectin-9
B7 CTLA-4 TIGIT CD155
CD94/NKG2A HLA-E/Qa-1 b
i
g
A Antigen n
n
t
e
u
m
t
e
r
c
o
c
a
t
T
c
d
i
v
e
e
n
s
g
i
c
i
t
n
e
a
T
e
e
e
c
r
e
v
p presenting cell l l N Naive T cell l l A Activated T cell l l Inhibitory signals T Tumor cell l l
Figure 1.

Interaction of naïve T cells during activation by the antigen presenting cell (APC) in the lymph node and the

expression of checkpoint inhibitors on the activated T cell upon interaction with the cancer cell in the suppressive

tumor microenvironment. (A) The process of T cell activation involves antigen presentation by the major

histocompatibility complex (MHC) molecules on the APCs to the corresponding T cell receptor (TCR) on naive

T cells. The interaction of costimulatory molecules CD28 and B7 is required for full activation, which is tightly

regulated by inhibitory checkpoints, like CTLA-4, to avoid collateral damage and autoimmunity . (B) In the tumor
6
microenvironment the cancer cell expresses ligands (e.g. B7, PD-L1, CD155, HLA-E) for inhibitory receptors present

on the activated T cell to inhibit its effector function (e.g. PD-1, CTLA-4, TIM3, TIGIT, NKG2A). Figures 1 was created
with BioRender.com.
IMMUNE THERAPY OF CANCER

Various methods of immune therapy have been developed to reinvigorate or initiate

immune responses against tumors, including vaccination, adoptive transfer of immune

cells and administration of monoclonal antibodies to specific tumor targets or inhibiting

immune checkpoint receptors. Therapeutic vaccination serves to activate the naïve T cell

repertoire but also to expand and reactivate the existing tumor specific T cell pool 32,33 .

Though vaccination shows increased frequencies and activation of tumor-specific T cells,

the success of vaccination has been hampered, predominantly due to the induction of

an immune-suppressive micromilieu in the tumor and to immune escape mechanism
of cancer cells, e.g. the expression of immune checkpoint ligands. PD-L1 expression, for
instance, can be induced by IFN-γ , which is expressed during an active anti-tumor immune

34
response. This has been referred to as a mechanism of adaptive immune resistance .

35
Blockade of immune checkpoints using monoclonal antibodies, initially shown for CTLA-4,

demonstrated tumor rejection, including preexisting tumors and resistance to a secondary

exposure in pre-clinical mouse models , motivating the introduction of blocking antibodies
36
against CTLA-4 in the clinic. The CTLA-4 monoclonal antibody ipilimumab was the first FDA

GENERAL INTRODUCTION 11