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IMMUNE CHECKPOINT: RECEPTOR BLOCKADE

Types of Immune Responses and regulatory mechanisms Revision:
Innate Immune response:
• Nonspecific
• Lacks memory
• Compromised of inflammatory cytokines, the complement system and phagocytes,
such as macrophages, neutrophils and dendritic cells

Adaptive immune response:
• Highly specific
• Development of memory cells
• Compromised of b and T lymphocytes, specifically CD8+ T lymphocytes and CD4+ T
helper lymphocytes (TH1 and TH2 cells)

Activation of T cell responses:
• Antigen-presenting cells (APCs), such as dendritic cells, can take up foreign antigens
and process the antigens, which are then bound to major histocompatibility (MHC)
molecules for presentation to T cells
...

• T cells become activated in the presence of signal 1 and co-stimulatory signals, which
are known as signal 2
...

• Activated T cells can kill indirectly by producing cytokines that act to initiate
apoptotic pathways in tumour and/or surrounding stromal cells
...


Regulation and suppression of T cell responses:
• Regulatory mechanisms can be intrinsic to T cells; examples are inhibitory immunecheckpoint molecules, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4)
and programmed cell death 1 (PD1)
...




T cell-mediated immunity:
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3
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e
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There are no longer any antigens presented to T cells and thus low immunogenicity
...
The tumours can also begin to present self-antigens thus misleading the immune
system and dampening down any possible immune response
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Tumour cells induce endocytosis and degradation of the antigens – antigenic
modulation
...
The tumour cells can also exploit the intrinsic immune checkpoints – i
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downregulation of T regulatory cells
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Tumour cells can secrete factors that create a physical barrier to the immune system
– tumour-induced privilege site
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Tumours co-opt/exploit inhibitory receptors and ligands (‘immune checkpoint’
molecules) that impair T cell survival, activation, proliferation and effector functions
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Immune checkpoint blockade (ICB) immunotherapy:
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Immune checkpoint therapy aims to
return T cell function and this can be measured via F-actin polymerization
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T cell activation requires 2 signals:
2
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- TCR signalling occurs when the TCR is engaged by cognate peptide (Ag)-MHC
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Signal 2: co-stimulatory signalling (i
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CD28) amplifies TCR signalling and the
recruitment of signalling molecules at the immune synapse to drive T cell activation
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4
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- T cell activation also induces expression of CTLA-4 and PD-1 (regulatory feedback
inhibition or the ‘brakes’ – deliver inhibitory signals)
- CTLA-4 and CD28 share ligands: CD80 and CD86, and thus compete during T cell
activation
...
There are multiple co-stimulatory (‘accelerators’) and inhibitory (‘brakes’)
interactions (signal 2) regulate T cell activation and responses
...
Signal 3: another major category of signals that regulate the activation of T cells
comes from soluble cytokines in the microenvironment
...
CTLA-4 engagement down-modulates the amplitude of T cell responses, largely by
inhibiting co-stimulation by CD28, with which it shares the ligands CD80 and CD86
...
CTLA-4 has a much higher affinity for both the ligands compared to CD28, so its
expression on activated T cells dampens CD28 co-stimulation by out-competing
CD28 binding (and possibly via depletion of CD80 and CD86 via “trans-endocytosis”)
...
Naïve and resting memory T cells express CD28, but not CTLA-4, on the cell surface,
allowing co-stimulation to dominate upon antigen recognition
...
However, CTLA-4 is rapidly mobilized to the cell surface from intracellular protein
stores, allowing feedback inhibition to occur within an hour after antigen
engagement and T cell activation
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CTLA-4 has a central role in maintaining immune tolerance in lymph node tissue
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Biology of immune checkpoint PD-1:
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2
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3
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PD-1
engagement directly inhibits TCR-mediated effector functions
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PD-1 has important physiological role in restraining collateral tissue damage during
T cell responses to infection
...
In addition, TILs commonly express heightened levels of PD-1 and are thought to be
“exhausted” due to chronic stimulation by tumour antigens
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Exhaustion or anergy of PD-1+ T cells is a form of inactivation in which the cell
remains alive but cannot be activated to execute an immune response
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Anergy is a reversible state
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There are two ligands for PD-1: PDL-1 and PDL-2, whereby the former is induced on
activated haematopoietic cells by IFN-gamma, and the latter is expressed on DCs and
some macrophages
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PD-1 ligands are upregulated in cancer and the receptor itself is highly expressed on
T cells from cancer patients (TILs), which leads to chronic stimulation by tumour
antigens and drives “exhaustion”
...
Co-option of the immune checkpoint network is a central process by which tumours
resist elimination by endogenous tumour specific T cells
...
There are two mechanisms by which the PD-L1 ligand is induced in cancer:
- Intrinsic resistance – refers to the constitutive expression of PD-1 ligands
because of genetic alterations or activation of oncogenic pathways in cancer
cells
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Constitutive expression of PD-1 ligands – amplification of chromosome 9p24
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b
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-

Adaptive resistance – refers to the induction of tumour PD-L1 expression in
response to cytokine IFN-gamma secreted by proximal T cells
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Adaptation of tumour cells upon sensing an inflammatory immune/T cell response
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Inhibition of T cells also mediated by PD-L1+ myeloid cells or DCs in the tumour
microenvironment
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Treating leukaemia (CLL) and lymphoma (DLBCL) tumour cells with anti-PD-L1 or T
cells with PD-1 prevents tumour inhibitory signalling and rescues anti-tumour T cell
activity
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ICB antibodies (anti-CTLA4, anti-PD-1 and anti-PD-L1) can unleash anti-tumour
immunity and mediate durable response in subsets of patients
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However, it remains unclear why the immunotherapy works within this subset of
patients
...
Strategies to maintain activated
tumour-specific T cells include the
use of blocking monoclonal
antibodies
...
Such as antibodies targeting either
cytotoxic T lymphocyte-associated
protein 4 (CTLA-4) or PD-1, to
neutralize co-inhibitory receptors
...
Therefore, these antibodies that
block intrinsic inhibitory immune
checkpoints allow a sustained T
cell response, including an
increased production of cytokines,
such as TNF-alpha, IFN-gamma and
granzyme B
...
ICB immunotherapy has substantial clinical activity against melanoma and
lymphoma patients
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ICB immunotherapy allows anti-tumour T cells to kill (cytotoxicity) target tumour
cells displaying a tumour antigen
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This is demonstrated by an increase (after ICB immunotherapy) in:
- T cell F-actin immune synapse area
- Percentage of granzyme B polarization



Future of ICB immunotherapy: combine therapy
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Combine multiple ICB antibodies, i
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anti-CTLA-4 with anti-PD-1 or anti-PD-L1
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e
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Overall: immune agonists
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Conclusions:
à Immune checkpoints (ICs) refer to inhibitory pathways (i
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PD-L1 and PD-L2 ligands, and
CTLA-4 and PD-1 receptors) that normally maintain self-tolerance and prevent tissue
damage during immune responses
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à PD-1 ligands (PD-1 and PD-2) are up-regulated in tumour tissue (tumours co-opt IC
pathways as a major mechanism to suppress T cell responses) while PD-1 and CTLA-4
receptors are highly expressed on tumour-infiltrating lymphocytes (T cells)
...


à ICB immunotherapy has the potential to unleash anti-tumour T cell immunity in patients
and is a new weapon against cancer (currently used in some liquid tumours but in a subset
of patients)

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