PD-L1 is an informative immunotherapy biomarker: Aberrant expression of PD-L1 on tumor cells and immune cells in the tumor microenvironment impedes anti-tumor immunity, allowing tumors to grow and metastasise.
PD-L1 is a transmembrane protein that down-regulates immune responses through binding to its two inhibitory receptors, programmed death-1 (PD-1) and B7.1. PD-1 is an inhibitory receptor expressed on T cells following T-cell activation, which is sustained in states of chronic stimulation such as in chronic infection or cancer.1 Binding of PD-L1 with PD-1 inhibits T cell proliferation, cytokine production and cytolytic activity, leading to the functional inactivation or exhaustion of T cells. B7.1 is a molecule expressed on antigen presenting cells and activated T cells. PD-L1 binding to B7.1 on T cells and antigen presenting cells can mediate down-regulation of immune responses, including inhibition of T-cell activation and cytokine production.2 PD-L1 expression has been observed in immune cells and tumor cells.3,4 Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor immunity, resulting in immune evasion.1 Therefore, interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific T cell immunity suppressed by the expression of PD-L1 in the tumor microenvironment.
References
1 Blank, C and Mackensen, A, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745.
2 Butte MJ, Keir ME, Phamduy TB, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27(1):111-122.
3 Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365-1369.
4 Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563-567.
References
1 NCI Dictionary of Cancer Terms. Tumor microenvironment. http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=561725
2 AACR. The Function of Tumor Microenvironment in Cancer Progression. http://www.aacr.org/Meetings/Pages/MeetingDetail. aspx?EventItemID=73#.V6pCFPkrKaE
3 Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y.BMC Med. New horizons in tumor microenvironment biology: challenges and opportunities. 2015 Mar 5;13:45. doi: 10.1186/s12916-015-0278-7.
4 Galon J1, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006 Sep 29;313(5795):1960-4.
5 Blank, C and Mackensen, A, Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother, 2007. 56(5): p. 739-745).
6 Ventana Medical Systems Inc. VENTANA PD-L1 (SP142) Assay. Package Insert. http://www.ventana.com/product/1827?type=2357
The tumor microenvironment (TME) consists of different cellular, including immune cells, and non-cellular components in and around the tumor. The TME has been recognized to play a significant role in tumor progression.1,2
The TME shapes tumor evolution (whether the tumor regresses, develops resistance, evades the immune system and/or metastasizes) and consequently impacts patient outcomes.3 An association has been observed between the levels of tumor infiltrating immune cells, key components of the TME, and patient prognosis: a colorectal cancer study showed that higher levels of tumor infiltrating CD3+ immune cells were associated with better disease free survival.4
Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor immunity, resulting in immune evasion.5 Therefore, interruption of the PD-L1/PD-1 pathway represents an attractive strategy to reinvigorate tumor-specific T cell immunity suppressed by the expression of PD-L1 in the TME. This approach has proven effective: PD-L1 expression on immune cells in the TME has been shown to identify urothelial cancer patients and breast cancer patients (TNBC) who are most likely to benefit from atezolizumab an anti-PD-L1 drug.6
