Programmed Cell Death-1 (PD-1)

Programmed cell death-1 (PD-1) is an immune checkpoint molecule that belongs to the CD28 family, which also includes CTLA-4. PD-1 is expressed on T cells and functions as a negative regulator of helper and effector T cell activity. Its ligands, PD-L1 and PD-L2, are members of the B7 family and are expressed by antigen presenting cells as well as tissue type-specific cells throughout the body and cancer cells. Binding of PD-1 to its ligands activates an intracellular signaling cascade that results in the dephosphorylation of the T cell receptor or of CD28¹, and the consequent reduction in T cell activity. In healthy individuals, this pathway tunes the immune system to protect against autoimmunity by suppressing effector T cells and promoting the activity of regulatory T cells (Tregs)^{2, 3}.

PD-1 has been identified as an important regulator of anti-tumor immunity. In the cancer setting, the PD-1/PD-L1 pathway in particular has been implicated in suppressing the immune response that would otherwise lead to tumor clearance. Overexpression of PD-L1 by tumor cells is one of the mechanisms used by tumors to evade immune detection. T cells that attempt to enter the tumor microenvironment are rapidly inhibited when they encounter the PD-L1 expressed by the tumor. The PD-1 pathway was first understood to play a role in anti-tumor immunity in 2002, when a study in the murine P815 mastocytoma model showed that expression of PD-L1 by the tumor cells enhanced tumor growth and metastasis, while injection of a blocking antibody prevented this from occurring⁴.

Since then, the importance of the PD-1 pathway in anti-tumor immunity has been a major focus of research in the field and has led to remarkable advances in the way that cancer is treated clinically⁵. Several anti-PD-1 therapies have been approved by the FDA for the treatment of different solid tumors⁵. (Several anti-PD-L1 therapies are also FDA approved). Indeed, anti-PD-1 treatments were among the first wave of checkpoint blockade immunotherapies that have revolutionized the way that cancer is treated⁶. Cancers that can be treated with anti-PD-1 antibodies include melanoma, lung cancer, bladder cancer, ovarian cancer, lymphoma, squamous cell carcinoma, renal cell carcinoma, and more^6–8. Some of these cancers, such as metastatic melanoma and ovarian cancer, were notoriously difficult to treat before the introduction of anti-PD-1 therapies.

Anti-PD-1 immunotherapy is sometimes given in conjunction with a CTLA-4-blocking antibody, a combination which can benefit patients independent of whether the tumor expresses PD-L1⁹. Conversely, an early clinical trial in metastatic melanoma showed that for patients treated with anti-PD-1 antibody alone, the response rate is more than double for patients whose tumors express PD-L1 compared to patients whose tumors do not¹⁰.

However, not all patients whose tumors express PD-L1 will respond to anti-PD-1 therapy⁶, and some patients who initially respond will develop resistance to the treatment¹¹. Other biomarkers that are being investigated to predict which patients will respond to anti-PD-1 immunotherapy include the immune signature of the tumor prior to treatment, including the ratio of effector CD8 T cells to Tregs, the expression of interferon gamma, or the amount of T cell infiltration into the tumor microenvironment¹². An existing immune presence in the tumor is predictive of a better response to treatment⁶, and T cell exhaustion is one marker of resistance to treatment¹¹. Despite the success of anti-PD-1 therapies in the clinic, these outstanding questions mean that more research is necessary to truly understand how anti-PD-1 and other checkpoint blockade immunotherapies can benefit the most patients.