Explore PD-L1

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  • Pathway Overview
  • Role In Cancer
  • Targeting PD-L1
  • PD-L1 as a Biomarker
Pathway Overview

Under normal conditions, the PD-L1 pathway plays an important role in maintaining immune homeostasis1

PD-L1 and PD-L2 are inhibitory ligands expressed on immune cells and other tissues.2,3

  • PD-L1 is broadly expressed in multiple tissue types, including haematopoietic, endothelial, and epithelial cells1,2
  • PD-L2 has more restricted expression on immune cells and in organs such as the lung and colon1-3

PD-L1 and PD-L2 bind to specific receptors on T cells, which downregulates cytotoxic T-cell activity and protects normal cells from collateral damage.1,4

PD-L1 binds to PD-1 and B7.15

PD-L1 ligand

PD-L2 binds primarily to PD-15

PD-L2 ligand

  • PD-1 is a receptor expressed primarily on activated T cells5
  • B7.1 is a receptor expressed on dendritic cells and also on activated T cells5
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Role In Cancer

Tumours can exploit the PD-L1 pathway to inhibit the antitumour immune response2,6

PD-L1 is broadly expressed on the surface of tumour cells and immune cells across cancer types—including breast, colorectal, lung, and renal.2,7

  • Adaptive PD-L1 expression is induced on tumour cells or tumour-infiltrating immune cells in response to interferon gamma produced by activated T cells6
  • Intrinsic PD-L1 expression is constitutively expressed by tumour cells in some cancer types, driven by genomic amplification or oncogenic driver mutations6

PD-L1 expression can protect tumours from cytotoxic T cells, providing tumours with a mechanism of immune escape. Expression of PD-L1 inhibits the antitumour immune response in 2 ways.2,5,7

PD-L1 may deactivate cytotoxic T cells in the tumour microenvironment 2,7

PD-L1 binds to its receptor PD-1, deactivating cytotoxic T-cells.2,7

  • Once deactivated, T cells remain inhibited in the tumour microenvironment2
PD-L1 pathway
PD-L1 may also prevent priming and activation of new T cells in the lymph nodes 2,6,8

When B7.1 on dendritic cells binds to CD28 on T cells, a costimulatory signal is delivered that leads to T-cell priming and activation. However, B7.1 has a higher affinity for PD-L1.2,6-8

  • PD-L1 expressed on T cells in the lymph nodes can bind to B7.1 on dendritic cells2,7,8
  • This binding prevents B7.1/CD28 interactions and dampens activation of new antitumour T cells2,5
PD-L1 pathway
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Targeting PD-L1

Inhibition of the PD-L1 pathway may invigorate antitumour T-cell activity2

Data suggest that PD-L1 may be one of the primary immunosuppressive drivers in multiple types of cancers. Preventing PD-L1 from binding to PD-1 and B7.1 can invigorate antitumour T-cell activity and enhance T-cell priming, leading to T-cell–mediated tumour killing2,4,7,9

  • Preventing PD-L1 from binding to PD-1 may invigorate suppressed T cells to kill tumour cells in the tumour microenvironment2
  • Preventing PD-L1/B7.1 interactions may enhance T-cell priming and activation in the lymph nodes2,7
Active T cell
Tumour cell

Preclinical studies suggest PD-L2 is primarily expressed on normal tissues and immune cells, protecting them during an immune response to maintain immune homeostasis. PD-L1 and PD-L2 can both bind to PD-1, which may lead to T-cell deactivation.1-3,10

  • Preclinical data suggest that targeting PD-L1 does not inhibit PD-L2/PD-1 interactions1,2
  • Therefore, targeting PD-L1 can preserve immune homeostasis in normal tissue by sparing the interaction of PD-L2 with PD-12
Inactive T cell
Epithelial cell

Roche is exploring the synergistic potential of targeting PD-L1 and other pathways in rational combinations that address multiple immune escape mechanisms.

The PD-L1 pathway is only one of many sources of immunosuppression in the tumour microenvironment.9 Because tumours employ multiple mechanisms to evade the immune response, an approach involving a combination of immunotherapy targets to re-establish proper antitumour T-cell activity may provide therapeutic benefit.9,11

In immune desert and immune excluded tumours, activated antitumour T cells need to be generated and recruited into the tumour microenvironment to initiate T-cell–mediated tumour killing.9,11,12*

  • Combination approaches that target escape mechanisms at earlier stages in the cancer immunity cycle, as well as PD-L1 in the tumour microenvironment, may be required to restore antitumour immune activity9

In inflamed tumours, preexisting immunity exists but is held in check. In some cases, PD-L1 inhibition alone may be sufficient to restore T-cell activity. In other cases, PD-L1 inhibition may be insufficient due to the presence of other immunosuppressive factors.9,11*

  • Combination approaches that target complementary pathways, as well as PD-L1, may provide synergistic potential in further invigorating T-cell activity9
*Mapping of pathways to phenotypes based on current lead hypotheses. Does not preclude activity in other phenotypes.

Roche is actively investigating the potential of targeting the PD-L1 pathway alone, and in combination with other pathways, in cancer immunotherapy research across multiple tumour types.

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PD-L1 as a Biomarker

PD-L1 expression may be an important facilitator of tumour growth and survival2,5,7,13

PD-L1 expression has been detected on tumour cells and tumour-infiltrating immune cells. Both may lead to the inhibition of activated T cells.2,5

PD-L1 on tumour cells

PD-L1 on tumour cells

PD-L1 on tumour-infiltrating immune cells

 PD-L1 on tumour-infiltrating immune cells

PD-L1 is a potential biomarker2,14

As a primary driver of immunosuppression in the tumour microenvironment, the identification of PD-L1 on tumour cells and tumour-infiltrating immune cells may be an important consideration for cancer immunotherapy research.2,5,7,13

Roche is actively investigating PD-L1 as well as other tissue-based and blood-based biomarkers and is committed to pursuing the potential of personalised cancer immunotherapy for cancer patients

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  1. 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. PMID: 22236695
  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. PMID: 23087408
  3. Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ. Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol. 2012;656340. PMID: 22611421
  4. Park JJ, Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 2010;116:1291-1298. PMID: 20472828
  5. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. PMID: 18173375
  6. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;274:450-461. PMID: 25858804
  7. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1-10. PMID: 23890059
  8. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7.1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111-122. PMID: 17629517
  9. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27:1492-1504. PMID: 27207108
  10. Akbari O, Stock P, Singh AK, et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell dependent airway hyperreactivity in opposing directions. Mucosal Immunol. 2010;3:81-91. PMID: 19741598
  11. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321-330. PMID: 28102259
  12. Hegde PS, Varanikas V, Evers S. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin Cancer Res. 2016;22:1865-1874. PMID: 27084740
  13. 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. PMID: 23511566
  14. Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023-5039. PMID: 27574444

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