CD27: An Emerging Target for Cancer Immunotherapy

Immune checkpoint molecules such as CTLA-4, PD-(L)1, and CD27, are a common target of immunotherapies against solid tumors. Targeting these molecules leads to the (re)activation of an immune response against a tumor, typically by blocking an inhibitory signal coming into the immune cell from either tumor cells or suppressive immune cells within the tumor microenvironment. The most well-known and earliest targets of checkpoint immunotherapies, targeting the PD-1/PD-L1 and CTLA-4 pathways, follow this mechanism and are known as checkpoint blockade immunotherapies. Immunotherapies that target CD27 function differently.

CD27 is expressed on conventional naïve and memory T cells, gamma-delta T cells, and effector and helper T cells immediately following antigen exposure but not at later stages of the primary immune response^1,2. CD27 is also expressed on B cells and NK cells, the other immune cells of lymphocytic origin. The ligand for CD27 is CD70, which is also expressed on T cells as well as B cells and dendritic cells. Both of these molecules belong to the TNF superfamily; CD27 is also known as TNFRSF7 and CD70 as TNFSF7. The interaction between CD27 and CD27 provides activation and proliferation signals to the CD27-expressing T cell^2,3.

Unlike checkpoint blockade immunotherapies, immunotherapies targeting CD27 are typically agonistic. These therapies include agonistic anti-CD27 antibodies or CD70⁴. In a model of B cell lymphoma, treatment with an agonistic anti-CD27 antibody led to increased production of CCL3, CCL4, and CCL5, chemokines that recruit myeloid cells, by T and NK cells⁵. The myeloid cells recruited to the tumor site were phagocytic and capable of attacking the lymphoma cells. CD27 agonists have also made it into human clinical trials for hematologic cancers⁶. A small phase 1 clinical trial in lymphoma resulted in one patient with a complete response to therapy and three patients with stable disease. Furthermore, some of the patients who responded to therapy displayed CD27- tumor cells but CD27+ immune infiltrates, suggesting that agonizing CD27 is an effective therapy when it can act on intratumoral immune cells.

However, some hematologic cancers express CD27, in which case antagonistic anti-CD27 treatments are desirable. An antibody targeting human CD27 competes with CD70 for binding on tumor cells, inhibiting their proliferation, while activating T cells as a "signal 2" to TCR stimulation⁷.

Targeting the CD27/CD70 pathway is also being investigated in solid tumors. A phase 1/2 trial of anti-CD27 agonist in combination with the anti-PD-1 immunotherapy nivolumab showed that about half of patients had a partial response or stable disease, and this was correlated with increased presence of CD8+ T cells within the tumor microenvironment⁸. A phase 2 clinical trial looking at CD27 agonism as a therapy for non-small cell lung cancer is underway. While studies into immunotherapies targeting CD27 are ongoing, it is a promising target that may function best in combination with other immunotherapies⁹.