Effective cancer immunotherapy further linked to regulating a cell
'suicide' gene

Date:
September 2, 2020
Source:
Johns Hopkins Medicine
Summary:
Researchers have added to evidence that a gene responsible for
turning off a cell's natural 'suicide' signals may also be the
culprit in making breast cancer and melanoma cells resistant to
therapies that use the immune system to fight cancer.



FULL STORY ========================================================================== Johns Hopkins Medicine researchers have added to evidence that a gene responsible for turning off a cell's natural "suicide" signals may also
be the culprit in making breast cancer and melanoma cells resistant
to therapies that use the immune system to fight cancer. A summary of
the research, conducted with mice and human cells, appeared Aug. 25 in
Cell Reports.


==========================================================================
When the gene, called BIRC2, is sent into overdrive, it makes too much,
or an "overexpression," of protein levels. This occurs in about 40% of
breast cancers, particularly the more lethal type called triple negative,
and it is not known how often the gene is overexpressed in melanomas.

If further studies affirm and refine the new findings, the researchers
say, BIRC2 overexpression could be a key marker for immunotherapy
resistance, further advancing precision medicine efforts in this area
of cancer treatment.

A marker of this kind could alert clinicians to the potential need
for using drugs that block the gene's activity in combination with immunotherapy drugs to form a potent cocktail to kill cancer in
some treatment-resistant patients."Cancer cells use many pathways to
evade the immune system, so our goal is to find additional drugs in
our toolbox to complement the immunotherapy drugs currently in use,"
says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of
Genetic Medicine, Pediatrics, Oncology, Medicine, Radiation Oncology and Biological Chemistry at the Johns Hopkins University School of Medicine,
and director of the Vascular Program at the Johns Hopkins Institute for
Cell Engineering.

Semenza shared the 2019 Nobel Prize in Physiology or Medicine for the
discovery of the gene that guides how cells adapt to low oxygen levels,
a condition called hypoxia.

In 2018, Semenza's team showed that hypoxia essentially molds cancer
cells into survival machines. Hypoxia prompts cancer cells to turn on
three genes to help them evade the immune system by inactivating either
the identification system or the "eat me" signal on immune cells. A cell surface protein called CD47 is the only "don't eat me" signal that blocks killing of cancer cells by immune cells called macrophages. Other cell
surface proteins, PDL1 and CD73, block killing of cancer cells by immune
cells called T lymphocytes.

These super-survivor cancer cells could explain, in part, Semenza says,
why only 20% to 30% of cancer patients respond to drugs that boost the
immune system's ability to target cancer cells.



==========================================================================
For the current study, building on his basic science discoveries, Semenza
and his team sorted through 325 human genes identified by researchers
at the Dana Farber Cancer Institute in Boston whose protein products
were overexpressed in melanoma cells and linked to processes that help
cancer cells evade the immune system.

Semenza's team found that 38 of the genes are influenced by the
transcription factor HIF-1, which regulates how cells adapt to hypoxia;
among the 38 was BIRC2 (baculoviral IAP repeat-containing 2), already
known to prevent cell "suicide," or apoptosis, in essence a form of
programmed cell death that is a brake on the kind of unchecked cell
growth characteristic of cancer.

BIRC2 also blocks cells from secreting proteins that attract immune cells,
such as T-cells and natural killer cells.

First, by studying the BIRC2 genome in human breast cancer cells,
Semenza's team found that hypoxia proteins HIF1 and HIF2 bind directly
to a portion of the BIRC2 gene under low oxygen conditions, identifying
a direct mechanism for boosting the BIRC2 gene's protein production.

Then, the research team examined how tumors developed in mice when they
were injected with human breast cancer or melanoma cells genetically
engineered to contain little or no BIRC2 gene expression. In mice injected
with cancer cells lacking BIRC2 expression, tumors took longer to form,
about three to four weeks, compared with the typical two weeks it takes
to form tumors in mice.



==========================================================================
The tumors formed by BIRC2-free cancer cells also had up to five times
the level of a protein called CXCL9, the substance that attracts immune
system T- cells and natural killer cells to the tumor location. The longer
the tumor took to form, the more T-cells and natural killer cells were
found inside the tumor.

Semenza notes that finding a plentiful number of immune cells within a
tumor is a key indicator of immunotherapy success.

Next, to determine whether the immune system was critical to the stalled
tumor growth they saw, Semenza's team injected the BIRC2-free melanoma
and breast cancer cells into mice bred to have no functioning immune
system. They found that tumors grew at the same rate, in about two weeks,
as typical tumors. "This suggests that the decreased tumor growth rate associated with loss of BIRC2 is dependent on recruiting T-cells and
natural killer cells into the tumor," says Semenza.

Finally, Semenza and his team analyzed mice implanted with human breast
cancer or melanoma tumors that either produced BIRC2 or were engineered
to lack BIRC2.

They gave the mice with melanoma tumors two types of immunotherapy
FDA-approved for human use, and treated mice with breast tumors with
one of the immunotherapy drugs. In both tumor types, the immunotherapy
drugs were effective only against the tumors that lacked BIRC2.

Experimental drugs called SMAC mimetics that inactivate BIRC2 and other
anti- cell suicide proteins are currently in clinical trials for certain
types of cancers, but Semenza says that the drugs have not been very
effective when used on their own.

"These drugs might be very useful to improve the response to immunotherapy drugs in people with tumors that have high BIRC2 levels," says Semenza.


========================================================================== Story Source: Materials provided by Johns_Hopkins_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Debangshu Samanta, Tina Yi-Ting Huang, Rima Shah, Yongkang Yang,
Fan Pan,
Gregg L. Semenza. BIRC2 Expression Impairs Anti-Cancer Immunity
and Immunotherapy Efficacy. Cell Reports, 2020; 32 (8): 108073 DOI:
10.1016/ j.celrep.2020.108073 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902182435.htm

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