Immune cells infiltrating tumors may play bigger cancer role than
previously thought

Date:
June 22, 2020
Source:
University of California - San Diego
Summary:
Researchers uncovered in mice how a molecule involved in cells'
response to stress determines whether macrophages promote
inflammation in the tumor microenvironment. Inflammation is known
to promote tumor growth, making this molecule an attractive target
for drug development.



FULL STORY ==========================================================================
Most traditional cancer therapies target either the tumor cells themselves
or indiscriminately kill any rapidly dividing cell. New findings by
researchers at University of California San Diego School of Medicine
indicate that manipulating macrophages, a type of immune cell found
abundantly in the tissues surrounding a tumor, could also be a viable
strategy for treating cancer.


==========================================================================
The study, published June 10, 2020 in PLoS Biology, is the first to
uncover the role a molecule called IRE1a plays in determining whether macrophages promote inflammation in the tissues surrounding cancer cells
-- a region known as the tumor microenvironment -- and throw off the
ability of other immune cells to fight cancer. Inflammation is known
to promote tumor growth, making IRE1a an attractive target for future
study and drug development.

"We've known that it takes a toll on a person's ability to fight cancer
when the tumor microenvironment is not properly regulated, when there's
a mix of pro-and anti-inflammatory macrophages," said senior author
Maurizio Zanetti, MD, professor of medicine at UC San Diego School
of Medicine and head of the Laboratory of Immunology at UC San Diego
Moores Cancer Center. "What we discovered here is how that happens,
and a potential way to reverse it." IRE1a is a key regulator of the
unfolded protein response, a cellular process that mammalian cells use
to deal with stress. Life in the tumor microenvironment is stressful
for immune and cancer cells, where they may be cut off from oxygen and nutrients. IRE1a and the unfolded protein response can often determine
whether a cell survives under these conditions.

In the new study, Zanetti and team show for the first time that IRE1a
and the unfolded protein response are also responsible for immune cell malfunction in the tumor microenvironment. The researchers found that
IRE1a regulates macrophage activation, determining whether these abundant immune cells secrete molecules that increase inflammation and at the
same time produce signals that suppress the immune system. They also
discovered that IRE1a boosts levels of PD-L1, a molecule that inhibits
other immune cells.

To corroborate their findings in mice, Zanetti and team looked for IRE1a patterns in genomic data available in The Cancer Genome Atlas (TCGA),
the National Institutes of Health's database of genomic information from thousands of human tumors. They found that in human breast and cervical cancers, the presence of macrophage IRE1a predicts the presence of PD-L1.

IRE1a's newly discovered role in regulating PD-L1 is significant because
the interaction between PD-L1 on tumor cells and its receptor on immune
cells tells the immune system to leave tumor cells alone. Checkpoint inhibitors, a type of cancer immunotherapy, treat cancer by blocking
that interaction, and thus boosting the immune system's ability to fight
off cancer. Other recent studies have shown that a person's response
to anti-PD-L1 immunotherapy depends on the PD-L1 present on their
macrophages, not on their tumor cells.

What this means, Zanetti said, is that a therapeutic drug that inhibits macrophage IRE1a might work indirectly as a checkpoint inhibitor --
less IRE1a could mean less PD-L1, removing the brake and allowing a
person's immune system to better attack tumor cells on its own.

To test this approach, the team engineered mice that lack the IRE1a gene
in their macrophages. These IRE1a-deficient mice survived melanoma better
than control mice.

"The implication for therapy is that, down the line, we might be able
to locally inhibit IRE1a to specifically prevent the mis-regulation of
the macrophages that infiltrate tumors and thus tip the balance in favor
of the immune system rather than the tumor," Zanetti said. "There is an
urgent need to develop IRE1a inhibitors as therapeutics for humans."

========================================================================== Story Source: Materials provided by
University_of_California_-_San_Diego. Original written by Heather
Buschman, PhD. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Alyssa Batista, Jeffrey J. Rodvold, Su Xian, Stephen C. Searles,
Alyssa
Lew, Takao Iwawaki, Gonzalo Almanza, T. Cameron Waller, Jonathan
Lin, Kristen Jepsen, Hannah Carter, Maurizio Zanetti. IRE1a
regulates macrophage polarization, PD-L1 expression, and
tumor survival. PLOS Biology, 2020; 18 (6): e3000687 DOI:
10.1371/journal.pbio.3000687 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200622160257.htm

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