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THE CANCER IMMUNITY CYCLE
Active cytotoxic T cell
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The cancer immunity cycle
The process by which the immune system kills cancer cells is described by the cancer
immunity cycle.1 Cancer immunotherapy research seeks to understand how to utilise the
body’s adaptive immune defence against cancer’s ability to evolve and evade destruction.2
Steps 1-3: Initiating and propagating anticancer immunity1
Dendritic cells capture cancer antigens and then prime and activate cytotoxic T cells.
1
Steps 4-5: Accessing the tumour1
Activated T cells infiltrate the tumour microenvironment.
Steps 6-7: Cancer-cell recognition and initiation of cytotoxicity1
Cancer antigens
T cells can recognise and kill target cancer cells, causing the release of additional
cancer antigens from the tumour.
W IT
Cancer antigens
HIN
T HE T
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U M OU R MICR O ENVIR ON M E
Tumour
apoptosis
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5
PD-L1 IN CANCER
Programmed death-ligand 1 (PD-L1):
an inhibitory immune pathway exploited by cancer
Cancer can evade the body’s immune response. Many tumours do this by expressing the inhibitory ligand
PD-L1 on tumour cells and tumour-infiltrating immune cells. Under normal conditions, the PD-L1 pathway can help
maintain immune homeostasis. In cancer, the PD-L1 pathway can protect tumours from cytotoxic T cells by disrupting
the cancer immunity cycle in two ways.1-4
Within the lymph nodes
PD-L1 may inhibit cancer immunity cycle propagation in the lymph nodes
Expression of PD-L1 on tumour-infiltrating immune cells can prevent the priming and activation of new cytotoxic
T cells in the lymph nodes and subsequent recruitment to the tumour.1-3
PD-L1 expression is upregulated
on dendritic cells within the
tumour microenvironment.2,3
PD-L1 binds to B7.1 and PD-1
receptors on T cells, suppressing
activation.3
PD-L1–expressing dendritic
cells travel from the tumour site
to the lymph node.5
Dendritic cell
B7.1
PD-L1
Inactive
cytotoxic
T cell
PD-L1
PD-1
Cancer
antigens
PD-L1
Tumour
cell
Within the tumour microenvironment
PD-L1 may inhibit cytotoxic T cell activity in the tumour microenvironment
Cancer
antigens
Upregulation of PD-L1 can inhibit the last steps of the cancer immunity cycle by deactivating cytotoxic
T cells in the tumour microenvironment.1
Activated T cells in the tumour
microenvironment release
interferon gamma.2
PD-L1 binds to T cell receptors B7.1 and
PD-1, deactivating cytotoxic T cells. Once
deactivated, T cells remain inhibited in
the tumour microenvironment.1,2
As a result, tumour cells and
tumour-infiltrating immune cells
express PD-L1.2
B7.1
PD-L1
PD-L1
PD-1
PD-L1
Inactive
cytotoxic T cell
Tumour cell
PD-L1 IN CANCER
PD-L1 AS AN IMPORTANT TARGET
The PD-L1 pathway is an important target in cancer research
Data suggest that PD-L1 may be one of the primary immunosuppressive drivers in multiple types of cancer.
Blocking PD-L1 can result in the restoration of anti-cancer T cell activity and enhanced T cell priming.2,3
Epithelial cell
PD-L1
Active T cell
PD-1
Active
cytotoxic T cell
Macrophage
PD-L1
4
3
B7.1
TCR
PD-L1 interference affects B7.1 and PD-1 binding2,3
2
PD-1
WIT
HIN
Inactive T cell
PD-L2
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SEL
ES
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WIT
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PD-L1
Tumour cell
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MHC
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OD
PD-L1
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PH
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LY
PD-L1 interference should not affect
PD-L2 interactions
• Interfering with PD-L1 activity on tumor cells and tumor-infiltrating
immune cells may prevent suppressive signaling through B7.1 and PD-1 • PD-L2 is another ligand primarily expressed on normal tissues and
on activated T cells.2,3
immune cells, protecting them during an immune response to maintain
– Preclinical studies suggest that
preventing
both
interactions
may
immune
by by
preclinical
studies2,6-8
The
process
by
which
the
immune
system
kills homeostasis,
cancer cellsasissuggested
described
the cancer
propagate T cell activity2
• Direct targeting of PD-L1 (unlike the targeting of PD-1) leaves the PD1
immunity cycle. Cancer immunotherapy research seeks to understand how to utilise the
L2/PD-1 interaction intact, potentially preserving
body’s adaptive immune defence against
cancer’s
abilityhomeostasis
to evolve 2,8and evade destruction.2
peripheral
immune
• Preclinical studies suggest that interfering with PD-L1 activity does not
Dendritic cell
inhibit PD-L2/PD-1 interactions2,6
2,6
The cancer immunity cycle
PD-L1 is a potential
predictive biomarker for
Steps 1-3: Initiating and propagating anticancer immunity
Dendritic cells capture
cancer antigens and in
then prime
and activate
cytotoxic T cells.
immune checkpoint
inhibitors
many
cancers
1
5
Roche is actively investigating
PD-L1
as a Accessing
potential predictive
Steps
4-5:
thebiomarker
tumourfor1 immune checkpoint inhibitors
in oncology research and isActivated
committed
to
pursuing
the
potential
of personalised cancer immunotherapy for
T cells infiltrate the tumour microenvironment.
cancer patients.
Steps 6-7: Cancer-cell recognition and initiation of cytotoxicity1
Cancer antigens
T cellsbeen
can recognise
and killon
target
cancer cells,
the release of additional
PD-L1 expression has
detected
tumour
cellscausing
and tumour-infiltrating
1,9
cancer antigens from the tumour.
immune
cells
1
Tumour
cell
Tumour10
Tumour-infiltrating immune cell10
PD-L1 on tumour cells (stained brown below) may lead to
the inhibition of activated T cells.2
PD-L1 on tumour-infiltrating immune cells (stained
brown below) may also inhibit T cell activation
and function.2,3
Cancer
antigens
T
WIT
EN
HIN
M
ON
THE T
UMOUR MICROENVIR
6
7
Tumour
apoptosis
Tumour-infiltrating
immune cells
THE CANCER IMMUNITY CYCLE
PD-L1 AS AN IMPORTANT TARGET
PD-L1: an inhibitory immune pathway exploited by cancer
• PD-L1 is an inhibitory ligand expressed by tumours
and tumour-infiltrating immune cells in many cancers2,4
B7.1
Inactive T cell
• PD-L1 binds to two receptors, B7.1 and PD-1,
to inhibit cytotoxic T cells2,3
PD-L1
PD-1
Tumour cell
PD-L1
• PD-L1 is a potential predictive biomarker for immune
checkpoint inhibitors in many cancers2
To learn more, please visit
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References: 1. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. 2. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1.
Clin Cancer Res. 2012;18:6580-6587. 3. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against
cancer. Br J Cancer. 2013;108:1560-1565. 5. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39:61-73. 6. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol.
2012;24:207-212. 7. Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol. 2012;2012:656340. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell
activation. Nat Immunol. 2001;2:261-268. 9. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021-1034. 10. Data on file. Genentech, Inc.
Published by
F. Hoffmann-La Roche Ltd
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© 2016
All trademarks mentioned herein are protected by law.
www.roche.com
May 2016
NP/aPDL1/1605/0034