Under normal circumstances, the immune system recognizes and
successfully fights cancer cells, eliminating them as they develop. However,
sometimes the process breaks down and tumors form, and now we know why.
Researchers at the Texas A&M Health Science Center found that when cancer
cells are able to block the function of a gene called NLRC5, they are able to
evade the immune system and proliferate, according to research published in
the Proceedings of the National Academy of Sciences (PNAS).
"We found the major mechanism of how cancer cells escape
from our immune system and form tumors," said Koichi Kobayashi, M.D.,
Ph.D., professor at the Texas A&M College of Medicine and a lead author on
the PNAS article. The discovery indicates NLRC5 as a novel biomarker for cancer
patient survival and therapeutic response, as well as a potential target for
new treatments.
"Cancer cells are born because of genetic changes, such as
mutations or rearrangement of pieces of different chromosomes," Kobayashi
said. "Because of this, all cancer cells have new, 'foreign' genes, which
host T-cells generally detect as tumor antigens. This anti-tumor system works
very well."
Kobayashi and his colleagues discovered several years ago that
NLRC5 regulates major histocompatibility complex (MHC) class I genes. These
genes code for molecules on the surface of cells that present fragments of
foreign proteins -- such as those from a virus or bacterium -- that have
invaded the cell. These fragments notify a part of the immune system called
cytotoxic T cells, triggering an immediate response from the immune system
against that particular foreign antigen.
The novel finding in this study is that the same system should
work to destroy cancer cells, but sometimes they find a way to disable the
NLRC5 gene, thus enabling them to evade the immune system and form tumors.
"If MHC class I antigen presentation does not work, cancer
cells will not be killed by T cells," said Sayuri Yoshihama, M.D., Ph.D.,
a fellow in Kobayashi's lab and first author of the paper. "We found that
function and expression of NLRC5 is reduced in cancer cells by various
mechanisms, and the result is immune evasion by cancer cells."
In fact, based on biopsy samples from 7,747 solid cancer
patients in The Cancer Genome Atlas (TCGA) database, expression of this NLRC5
gene is highly correlated with cancer patient survival in various cancer types
-- especially melanoma, rectal cancer, bladder cancer, cervical cancer and
head/neck cancer -- with patients who survive longer tending to have greater
expression of NLRC5. Among these, melanoma and bladder cancer displayed the
most striking differences, with 5-year survival rates of 36 percent and 34
percent in the NLRC5-low expression group compared with 71 percent and 62
percent in the NLRC5-high expression group, respectively.
"With this finding of NLRC5 as an important biomarker for
cancer, we can ultimately predict how long cancer patients can survive and how well
cancer treatments might work for them," Kobayashi said. It might be
especially relevant for melanoma patients, both because NLRC5 mutation rate is
relatively high and because its levels of expression are highly predictive of
survival for that cancer type.
The team plans to continue its research on the role of NLRC5 in
cancer and is actively developing plans for commercialization of technology
related to this discovery. A provisional patent application has been filed, and
plans are underway to develop and validate a test that can, based on NLRC5
expression levels, be used to predict cancer patient survival and therapeutic
response. The hope is that the test will give health care providers one more
tool for determining the best treatment strategy for cancer patients to
eliminate the burden of costly, unhelpful therapies.
Eventually, Kobayashi and his team hope this discovery might
also lead to new therapeutic strategies for cancer.
"If we can regulate the activation of NLRC5 or its
expression level, that could be a novel cancer treatment," Kobayashi said.
"We hope that in several years, our research may identify potential drug
candidates that can increase the levels of NLRC5 and thus help our own immune
systems better fight the cancer."
Still, he advises caution. This mechanism of evading the immune
system is not employed by every cancer cell, and the research still needs to be
replicated in an animal model.
Cancer isn't the only surprising disease that can be affected by
the immune system. Kobayashi's previous work in immune function and genetics
focused on inflammatory bowel disease, such as Crohn's disease. They also study
transplant medicine, trying to determine why some organs are rejected by the
new host.
"We now know why cancer cells can escape from our immune
system," Kobayashi said. "No other mechanism is as dramatic as we
found. We envision the NLRC5 biomarker as allowing physicians to evaluate and
determine the best treatment strategy for each cancer patient, thus leading to
better therapeutic outcomes for the more than 12 million people diagnosed with
cancer each year."
FIst page published as image at http://link.springer.com/article/10.1007/s13238-012-2109-3#/page-1 Expression
regulation and function of
NLRC5, Protein and Cell 2013,166-175
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http://www.fiercebiotech.com/research/mechanism-found-causes-cancer-cells-to-escape-from-immune-system?utm_medium=nl&utm_source=internal&mrkid=874279&mkt_tok=eyJpIjoiTURGaVltTTRPVEZqTlRobSIsInQiOiJRWlpJdWE3ZVU2R3ZHRDJLbXgwZnphQTVlM1BiWk9SY0tzNEpcL3JOeWU2R0tQNGNraG0zcjR6clwvbkdwVHp0cDVEQjVLdXRGNlJIcDlxbDRPVk92OGk1T1lkNitjOUd1d1wvWEJXRDZCVStNYz0ifQ%3D%3D
Mechanism found that causes cancer cells to escape from immune
system
by Ben Adams |
May
11, 2016 3:40am
Under normal circumstances,
the immune system recognizes and successfully fights cancer cells and
eliminates them as they develop, but sometimes the process breaks down and
tumors form--and now researchers have found out why.
According to a new paper
published in the Proceedings
of the National Academy of Sciences (PNAS),
the Texas
A&M Health Science Center found that when cancer cells are able to block
the function of a gene calledNLRC5,
they are able to evade the immune system and proliferate.
"We found the major
mechanism of how cancer cells escape from our immune system and form
tumors," said Dr. Koichi Kobayashi, a professor at the Texas A&M
College of Medicine and a lead author on the PNASarticle,
in a news
release. The discovery indicates NLRC5 as
a potential new biomarker for
cancer patient survival and therapeutic response--as well as a potential target
for new treatments.
"Cancer cells are born
because of genetic changes, such as mutations or rearrangement of pieces of
different chromosomes," Kobayashi said. "Because of this, all cancer
cells have new, 'foreign' genes, which host T-cells generally detect as tumor
antigens. This anti-tumor system works very well."
Kobayashi and his
colleagues discovered several years ago that NLRC5 regulates
major histocompatibility
complex (MHC) class I genes.
These genes code for
molecules on the surface of cells that present fragments of foreign
proteins--such as those from a virus or bacterium--that have invaded the cell.
These fragments then signal immune system components called cytotoxic T cells,
triggering an immediate response against that particular foreign antigen.
The study shows that the
same system should work to destroy cancer cells, but sometimes they find a way
to disable the NLRC5 gene,
thus enabling them to evade the
immune system and form tumors.
"If MHC class I
antigen presentation does not work, cancer cells will not be killed by T
cells," said Dr. Sayuri Yoshihama, a fellow in Kobayashi's lab and first
author of the paper, in the release. "We found that function and
expression of NLRC5 is reduced in cancer cells by various mechanisms, and the
result is immune evasion by cancer cells."
In fact, based on biopsy
samples from 7,747 solid cancer patients in The Cancer Genome Atlas (TCGA)
database, expression of thisNLRC5 gene
is highly correlated with cancer
patient survival in various cancer types--especially melanoma, rectal cancer,
bladder cancer, cervical cancer and head/neck cancer--with patients who survive
longer tending to have greater expression of NLRC5.
Among these, melanoma and
bladder cancer displayed the most striking differences, with 5-year survival
rates of 36% and 34% in theNLRC5 low-expression
group compared with 71% and 62% in the NLRC5 high-expression
group, respectively.
"With this finding of NLRC5 as
an important biomarker for cancer,
we can ultimately predict how long cancer patients can survive and how well
cancer treatments might work for them," Kobayashi said. It might be
especially relevant for melanoma patients, both because theNLRC5 mutation
rate is relatively high and
because its levels of expression are highly predictive of survival for that
cancer type.
The team plans to continue
its research on the role of NLRC5 in
cancer and said it is actively
developing plans for commercialization of the tech related to this discovery. A
provisional patent application has already been filed, and plans are underway
to develop and validate a test that, based on NLRC5 expression
levels, can be used to
predict cancer patient survival and therapeutic response.
The hope is that the test
will give healthcare providers one more tool for determining the best treatment
strategy for cancer patients to eliminate the burden of costly, unhelpful
therapies.
Eventually, Kobayashi and
his team said they hope this discovery might also lead to new therapeutic
strategies for cancer.
