Discover the PD-1 pathway and its role in cancer 105/15 -ONCO- 07/15

Discover the PD-1 pathway and its role in cancer 105/15 -ONCO- 07/15

Immunology in cancer The role of immunology in cancer Evolving knowledge of the immune system has provided a better understanding of its role in fighting certain types of cancer. 1 For example, many tumors express multiple antigens that are not expressed in normal tissue, suggesting the opportunity for immune responses. 2, 3 Although certain tumors can induce an immune response, some tumors can still 1, 4 evade immune surveillance and proliferate in immunocompetent patients. One of the contributing factors to tumor growth may be immune suppression within the tumor microenvironment as a result of tumor interaction with the immune system. 5, 6 2

Immunology in cancer Some tumors may evade the immune response by activating immune checkpoints. 1. Tumor cells express multiple antigens that are not expressed in normal tissue. 2,7 Immune Checkpoint Tumor Cell 4 Antigen 1 Antigen- Presenting Cell (APC) Antigen 2. Antigen-presenting cells capture the antigenic peptides and activate. antigen-specific T cells. 2 3. The activated T cells then destroy tumor cells through antitumor effector mechanisms. 5,6 Inactivated T Cell Major Histocompatibility Complex (MHC) 2 4. Some tumors are able to evade the immune response.one mechanism tumors may employ involves activating immune checkpoints, which function at different phases in the immune response to regulate T-cell activity 2, 7 3 Activated T Cell T-Cell Receptor 3

Immune checkpoint pathways can regulate T-cell activity during the body s 2,8 immune response Immune checkpoints, such as CTLA-4, PD-1, GITR, and LAG-3, function at di erent phases in the immune response to regulate the duration and level of the T-cell response. 2,8,9 CTLA-4 primarily regulates T cells during the priming phase (early stage) of activation in the lymph nodes and is thought to function as an o switch, broadly shutting down T-cell activity in order to limit autoimmunity. 2,10,11 PD-1 primarily regulates T-cell activity during the e ector phase of the immune response and can shut down the activity of antigen-speci c T cells in the tumor microenvironment. The normal role of PD-1 activation is thought to be the downregulation of T-cell activity in peripheral tissues in order to limit collateral tissue damage during the immune response. 2,8,10 Various additional immune checkpoints, such as GITR and LAG-3, are also being studied for their potential role in the antitumor immune response and tumor immune evasion. 2,9 LAG-3 is highly expressed on Treg cells (which help prevent autoimmunity), where it is thought to be important for amplifying immunosuppressive activity; LAG-3 is also associated with inhibition of e ector T-cell activity and may induce T-cell anergy. 2 GITR is a costimulatory immune checkpoint receptor that is thought to enhance T-cell proliferation and e ector function; activation of GITR may downregulate immunosuppressive activity of Treg cells. 9 CTLA-4=cytotoxic T-lymphocyte associated antigen 4; PD-1=programmed cell death protein 1; GITR=glucocorticoid-induced tumor necrosis factor receptor; LAG-3=lymphocyte activation gene 3. Immune checkpoint pathways 4

The PD-1 pathway is thought to primarily regulate the effector phase of T-cell activity. 10 Tumor Cell Activated T Cells PD-1 Inactivated T Cell Immune checkpoint pathways From N Engl J Med, Ribas, Tumor immunotherapy directed at PD-1, 366:2517 2519. Copyright 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 5

Tumors may evade the body s immune response by exploiting the PD-1 2, 8 checkpoint pathway Emerging research has identi ed PD-1 as an immune checkpoint pathway that tumor cells may exploit to evade immune surveillance. 7,8 Tumors may block immune responses via the PD-1 immune checkpoint pathway by expressing the dual PD-1 ligands PD-L1 and PD-L2. 7,12 14 PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumors to evade the immune response. 2,7,15,16 PD-L1 is expressed on many tumor cells and may downregulate tumor-specific T-cell activity by binding to PD-1 in the tumor microenvironment. 7,12,15 PD-L2 may also have a role in helping tumors evade the immune response. 15,17 The role of PD-1 in cancer PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2. 6

Tumor Microenvironment Major Histocompatibility Complex PD-L1 Engagement of the PD-1 receptor by its ligands PD-L1 and PD-L2 may downregulate T-cell activity in the tumor microenvironment. 7,8,15,16 PD-L2 PD-L1 PD-1 Receptors Antigen T-Cell Receptor PD-L1 and PD-L2 engage the PD-1 receptoron T cells in order to inactivate T cells and potentially block an immune response. 2,7,15,16 Inactivation Block Immune Response Activation T Cell The role of PD-1 in cancer 7

PD-L1 is expressed by some tumor cells Tumor cells have shown varying levels of PD-L1 expression. 14, 18-20 The significance of PD-L1 expression remains a focus of oncology research. 2 2 PD-L1 expression in cancer 8

Activated T Cell PD-1 Receptor PD-L1 Inactivated T Cell PD-L1 expression in cancer 9

Discover the PD-1 pathway and its role in cancer Evolving knowledge of the immune system has provided a better understanding of its role in fighting certain types of cancer. 1 Immune checkpoint pathways can regulate T-cell activity during the body s immune response. 2,8 Tumors may evade the body s immune response by exploiting the PD-1 checkpoint pathway. 2,8 Tumor cells have shown varying levels of PD-L1 expression; the significance of PD-L1 expression remains a focus of oncology research. 2,14,18 20 MSD Oncology is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway. MSD Oncology Copyright 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. ONCO-1121001-0000 08/14