- Immunotherapies known
inhibitors block interaction of PD-L1 protein on the surface of tumor
cells with the PD-1 protein found on T cells, and thereby making them
susceptible to host immune system attack.
- Check-point inhibitors, however are not
effective in all cancer types.
- Recent study identifies
Eya3 protein which can be targeted to make check-point inhibitors more
effective in triple negative breast cancer.
Targeting Eya3 protein (belonging to the Eya family of proteins) shown
to make check-point
inhibitors more effective in triple negative breast cancer. This finding is the
result of a University of Colorado Cancer Center study that hoped to determine what drove the breast
cancer cells to produce PD-L1 protein in the first place
in order to try
and make immunotherapy even more effective in combating cancer.
"People had shown that Eya3 was involved in immune responses to
viruses, but nobody had examined whether Eya3 could also play a role in evasion
of cancer cells from the immune system, nor did anyone know how it works,"
says Heide Ford, PhD, associate director of basic research at CU Cancer Center
and the David F. and Margaret Turley Grohne Chair in Basic/Translational Cancer
Analyzing Role Eya Family of Proteins in Cancer in
In order to understand how Eya proteins influenced a tumor cells
interactions with a host's immune system, Ford and his team used a special kind
of mouse model, termed immunocompetent mouse, in which mouse mammary tumor
cells (that resemble human breast cancers
), are injected into immunocompetent
‘Suppressing cancer cell production of Eya3 protein reduces PD-L1 formation by tumor which in turn promotes attack of tumor by the immune system.’
This enabled the scientist to explore not only what happens within
living cancer cells, but how these living cells interact in the presence of
host tumor microenvironment that surrounds them.
Findings of Study
Ford and her team saw a completely new action of Eya3 protein.
- In the immunocompetent
mouse models of triple negative breast cancer, the team found that
interfering with cancer cells' ability to make Eya3 protein led to a
decreased formation of PD-L1 protein and higher tumor infiltration by CD8+
immune T-cells (that attack and destroy the tumor).
- Thus, if a tumor did
not produce Eya3, it also did not make PD-L1, making it vulnerable to
attack by the immune system.
According to Ford, "We showed that Eya3 can regulate the immune
response to a tumor. In all of our systems, Eya3 was required for PD-L1
Could Eya3 protein be
only regulator of PD-L1?
Ford says, "I don't think so. I suspect there will be other ways to
regulate the protein. But in our three models, Eya3 was a key regulator of
PD-L1, which argues that Eya3 is potentially a main driver of PD-L1."
- When Ford and her
colleagues looked at human samples of triple negative breast cancer , they found that levels
of Eya3 corresponded to the level
of PD-L1 protein.
- Tumors that had high
levels of Eya3 had low levels of CD8+ T cell infiltration within the tumor.
the findings of the study have identified a potential target namely Eya3
protein which increases CD8+ T cell entry within the tumor and makes the host
immune system respond effectively to eliminate the tumor.
Other Links in Chain that Connect Eya3 Protein and PDL1
Other proteins have been identified which serve as a link between Eya3
and PD-L1 protein creating a rather complex network:
- For instance, the PP2a gene is normally a tumor
suppressor gene. However, in the presence of Eya3, the gene PP2a changed
roles and became a tumor promoter.
- Another protein
identified in this chain is the Myc
protein that is mutated in about 70 percent cancers. Several recent
studies have shown that Eya3 appeared to act via Myc protein to enhance
production of PD-L1 and thus suppress the immune system.
"Though the specifics of this complicated story remain to be defined,
the gist is that, "Eya3 may be how
PD-L1 is activated in triple-negative breast cancer,"
About the Eya Protein Family
The Eya family of proteins, including Eya3, has been the focus of
research in the Ford lab. The Eya proteins are critical for early embryonic
development, but most of them are silent in adult tissues.
The Eya protein family are complex molecules consisting of distinct
regions that each have distinct functions. Until now not many had looked at the
various actions of the different Eya regions within or especially outside the
tumor cell microenvironment.
Previous research including the Ford Lab have shown that when cancers
are able to re-stimulate the activity of Eya proteins, they function within
tumor cells to drive cell growth and proliferation.
What is Triple Negative Breast Cancer?
Triple negative breast cancer
does not contain estrogen or progesterone receptors or Her-2 receptors, thus
being negative for all three. About 10-20 percent of breast cancers are triple
Such cancers are difficult to treat as they do not respond to hormone
therapy or therapy that targets Her-2. Other alternative treatments are being
researched in addition to currently available standard chemotherapy.
In conclusion, this study symbolizes yet another effort aimed at making
cancer treatment, in particular immunotherapy more effective in triple negative
breast cancer and hoping to improve the outcome for the patient.
- Triple negative breast cancer - (http://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/types/triple-negative-breast-cancer)
- Who gets Triple Negative Breast Cancer - (http://www.breastcancer.org/symptoms/diagnosis/trip_neg)