CD70 is a protein on the surface of cells belonging to the Tumor Necrosis Factor (TNF) superfamily, which regulates cell survival and death. It acts as a ligand, a signaling molecule that binds to a specific receptor on another cell to transmit a message. While CD70 is a component of a healthy immune system, its persistent presence on the surface of certain cancer cells makes it a compelling target for therapeutic research. This distinct expression pattern effectively turns CD70 into a flag that can be selectively targeted by new-generation cancer treatments.
The Role of CD70 in Healthy Immune Function
The function of CD70 centers on its interaction with its dedicated receptor, CD27, creating the CD27/CD70 axis. This molecular partnership provides a co-stimulatory signal necessary for the adaptive immune response. When the immune system detects an invasion, CD70 temporarily appears on the surface of activated immune cells, such as T cells, B cells, and dendritic cells.
The interaction between CD70 and CD27 is fundamental for effective T cell activation, differentiation, and proliferation. Binding to the CD27 receptor helps amplify the initial immune response triggered by an antigen, ensuring T cells multiply sufficiently to combat a threat. This signaling is also required for the long-term survival and maintenance of memory T cells, which provide rapid protection against previously encountered pathogens.
In B cells, the CD27/CD70 axis aids in the development of B cell memory and the production of protective antibodies. The controlled, transient nature of CD70 expression is a regulatory mechanism that prevents the immune system from becoming overactive. Once the infection is cleared, CD70 expression rapidly disappears, switching off the aggressive immune response.
This tight regulation ensures the powerful immune response is limited in duration and scope, preventing damage to healthy tissues. Because CD70 expression is restricted in normal, non-lymphoid tissues, its presence is a reliable indicator of immune cell activation. This limited expression makes CD70 an attractive target for therapies aiming to destroy specific cell populations.
Aberrant CD70 Expression in Disease
In many forms of cancer, the control mechanisms governing CD70 expression fail, leading to its persistent and abnormal presence on malignant cells. This aberrant expression transforms CD70 from an immune regulator into a vulnerability for the cancer cell. The continuous display of CD70 has been observed in various malignancies, including hematological cancers like Non-Hodgkin Lymphoma (NHL) and solid tumors such as Renal Cell Carcinoma (RCC).
The mechanism behind this sustained expression often involves oncogenic signals, such as hypoxia-inducible factors (HIFs) stabilized in the tumor microenvironment. For instance, in clear cell RCC, the stabilization of HIF-2α (often due to a non-functional VHL gene) directly activates the transcription of the CD70 gene. This pathological process links the tumor’s aggressive biology to the presence of the CD70 protein.
The constant engagement of CD70 on the tumor cell with CD27 on nearby T cells drives a detrimental process for the immune response. This chronic stimulation leads to T cell exhaustion, where immune cells become functionally impaired and unable to mount an effective anti-tumor attack. Furthermore, sustained CD70 signaling promotes the expansion of regulatory T cells (Tregs), which actively suppress the immune response.
Tumor-expressed CD70 also facilitates immune evasion by inducing apoptosis, or programmed cell death, in effector T and B lymphocytes. This cytotoxic effect is achieved through the CD70/CD27 pathway, sometimes involving the intracellular protein SIVA, which initiates the caspase cascade responsible for cell death. By constantly presenting CD70, tumor cells actively dismantle the immune surveillance meant to eliminate them, promoting disease progression.
Specific cancers show high rates of CD70 positivity, making them strong candidates for targeted treatments. For example, a majority of Diffuse Large B-cell Lymphoma, Follicular Lymphoma, and Mantle Cell Lymphoma samples exhibit high levels of CD70 staining. Clear cell RCC specimens often show CD70 expression nearly double that of normal kidney tissue, confirming it as a potential biomarker and a therapeutic liability for these diseases.
CD70 as a Therapeutic Target
The limited expression of CD70 on healthy cells combined with its high and persistent expression on various tumor types establishes it as an ideal target for precision oncology treatments. Current strategies focus on interrupting the pathological CD70-CD27 signaling pathway and using the protein as an anchor point to deliver cell-killing agents directly to cancer cells. These approaches include monoclonal antibodies, antibody-drug conjugates (ADCs), and advanced cellular therapies.
Monoclonal Antibodies
Monoclonal antibodies (mAbs) are designed to bind directly to the CD70 protein on the cancer cell surface. These “naked” antibodies, such as cusatuzumab, exert their anti-tumor effect through several mechanisms. They can block CD70 from binding to its receptor CD27, reversing the immunosuppression caused by the cancer. They also recruit immune cells, like Natural Killer (NK) cells, to the tumor site, a process known as Antibody-Dependent Cellular Cytotoxicity (ADCC), which leads to the direct destruction of the CD70-expressing cell.
Antibody-Drug Conjugates (ADCs)
A more potent approach uses CD70 as a vehicle for targeted drug delivery through Antibody-Drug Conjugates (ADCs). ADCs, such as SGN-75, link a specific anti-CD70 antibody to a highly potent chemotherapy drug, like monomethyl auristatin F. Once the ADC binds to CD70 on the tumor cell surface, the entire complex is rapidly internalized by the cell.
After internalization, the linker connecting the antibody and the chemotherapy drug is cleaved, releasing the cytotoxic payload directly inside the cancer cell. This mechanism ensures the drug concentration is high within the tumor while minimizing systemic exposure and reducing the severe side effects associated with traditional chemotherapy. ADCs exploit the tumor cell’s expression of CD70, effectively turning the protein into a “Trojan horse” for its own destruction.
Cellular Therapies
The most advanced strategy involves cellular therapies, primarily Chimeric Antigen Receptor (CAR) T-cells, currently being investigated in clinical trials for CD70-positive cancers like RCC and gliomas. In this technique, a patient’s T cells are collected and genetically engineered in a laboratory to express a synthetic receptor designed to recognize and latch onto CD70.
Once infused back into the patient, these engineered CAR T-cells locate and destroy any cell displaying the CD70 protein. This approach offers a living drug capable of persistent tumor surveillance. However, a challenge for CD70-targeted CAR T-cells is fratricide, where the engineered T cells may inadvertently destroy each other due to low-level CD70 expression on activated T cells, requiring careful optimization of the therapy.