New Target for Cancer Immunotherapy Identified

A research team from Massachusetts General Hospital has identified a significant target for immune-oncology therapy-tumor necrosis factor receptor type II (TNFR2). The inhibition of these receptors was found to induce the immune system of cancer patients to fight against the developing tumor.

Tumor Necrosis Factor 2:

TNF2 is known to possess these characteristics:

• There is no death domain expressed on the receptor
• It induces a NF-kB activation that is long lasting
• TNFR2 activation of NF-kB is independent of the TNFR1 signaling
• TNFR2 is activated by tumor necrosis factor (TNF)
• TNFR2 is expressed on T cells that are immuno-suppressive as well as on many types of cancer cells.

The study published in the Journal Science Signaling tries to unearth a new target for cancer treatment. Dr. Denise Faustman who is the head of the Immunology Lab at Massachusetts General Hospital said that they had known for some time that there was increased expression of TNFR2 in the tumor micro-environment, especially on T cells.

Antibiotic Treatment of Cancer:

The use of antibody as a therapy for cancer is effective in two ways

• Targeting specific oncogenes: An example of this method of treatment occurs in breast cancer where the expression of Her2 oncogenes on the surface of the tumor cells is effective in blocking the growth signal using antibody therapy. However, not everyone expresses these oncogenes.
• Targeting patient’s immune system: Current approaches involve targeting the immune system of the host, rather than just specific oncogenes that are expressed.

Immune Checkpoint Inhibitor Antibodies

There are certain inhibitors for the immune system which include molecules like PD1 and CTLA4 receptors which could aid in the treatment of cancer cells. The only drawback is that these are expressed both on normal cells as well as cancerous cells. Targeting these inhibitors could lead to the development of an autoimmune condition.

Dr. Faustman and colleagues developed two new antibodies to TNFR2 which target an oncogene that is widely expressed and ready for killing cancer cells. When cells that express TNFR2 are selectively targeted, they restore the patient’s immune system which leads to renewed attack of the tumor cells.

Monoclonal Antibodies:

TNFR2 activation was inhibited by the research team by using antagonistic monoclonal antibodies which block the effects of the receptor rather than stimulating its activation. The studies found that

• Antibodies inhibited the proliferation of regulatory T cells (Tregs)
• This allowed the restoration of immune system of the host
• TNFR2 antibodies killed Tregs more potently
• Tregs were isolated from the fluid that surrounds the ovarian cancer metastases than Tregs from cancer-free individuals

The Tregs were found to be unique to the tumor environment which meant that it would not harm the normal healthy cells of the body. Dr. Faustman said that when they started work on these antibodies ten years ago, they focused on the role of the immune system as it was found to be associated with autoimmune disease type 1 diabetes. She further added "At the same time the oncology community was beginning to look at unlocking similar pathways in cancer. This project has given us the opportunity to look at other functions of the TNFR2 receptor beyond autoimmunity and collaborate across departments at MGH, including gynecologic oncology teams."

Two Birds with One Stone:

The blockage of the TNFR2 was found to boost the immune response against the tumor cells as well as kill the cells.

TNFR2 in Tumor cells

In a study conducted by Yan F et al and colleagues titled “Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients” and published in the journal Cancer Immunology Immunotherapy, the role of TNFR2 in tumor progression was detailed.

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The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs was found in a population of suppressive Treg population. The research team undertaking the study focused on the function of TNFR2 in the peripheral blood of patients with lung cancer.

• The peripheral blood of lung cancer patients showed higher expression of TNFR2.
• The expression of TNFR2 was correlated better than CD25(+) and CD127(-).
• Peripheral blood TNFR2(+) Tregs in the lung cancer patients was found to more proliferative and expressed higher levels of the immunosuppressive molecule, CTLA-4.
• Increased expression of TNFR2 on Tregs was associated with metastasis to distant target organs, lymphatic invasion, and a more advanced stage of lung cancer.

TNFR2 is a significant target in cancer therapy as there is expression of this receptor in a large number of cancer patients and inhibition will aid in inducing a better immune response.

References:

1. Expression of TNFR2 by regulatory T cells in peripheral blood is correlated with clinical pathology of lung cancer patients - (https://www.ncbi.nlm.nih.gov/pubmed/26280204)

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Source-Medindia