- A research team
from Massachusetts General Hospital has found that inhibition of tumor
necrosis factor receptor 2 stimulates the immune system of the host.
- The inhibition
aids in increasing immune response and is also found to kill tumor cells
- The antibodies
against tumor necrosis factor could be used in people with different types
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 Necrosis Factor
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.
‘Targeting tumor necrosis factor receptor 2 will aid in increasing immune response and aid in killing tumor cells directly’
The use of antibody as a therapy for cancer is effective
in two ways
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
patient's immune system: Current
approaches involve targeting the immune system of the host, rather than
just specific oncogenes that are expressed.
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
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
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
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
patients" and published in the journal Cancer Immunology
Immunotherapy, the role of TNFR2 in tumor progression was detailed.
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.
expression of TNFR2 on Tregs was associated with metastasis to distant
target organs, lymphatic invasion, and a more advanced stage of lung
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
- 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)