Internal differences: A new method for seeing into cells

Date:
August 12, 2020
Source:
Weizmann Institute of Science
Summary:
The new technology may help answer outstanding questions about
the immune system, cancer, Alzheimer's, and more.



FULL STORY ========================================================================== Invading cells' private space -- prying into their internal functions, decisions and communications -- could be a powerful tool that may help researchers develop new immunotherapy treatment for cancer. As reported
today in Cell, a research group at the Weizmann Institute of Science has developed a technology that enables them to see inside tens of thousands
of individual cells at once in greater details than ever before. The
group, headed by Prof.

Ido Amit of the Institute's Immunology Department, applied this method
to define the immune cells that infiltrate tumors, identifying a new
subset of innate immune cells that "collaborate" with cancer. Blocking
these inhibitory immune cells in mice greatly enhanced the anti-tumor
immune response, killing the cancer.


==========================================================================
Amit and his group had previously made significant inroads into seeing
into cells when they developed single cell RNA-sequencing -- a means of sequencing all of the RNA in thousands of individual cells at once. The
new technique, called INs-seq (intracellular staining and sequencing)
-- developed in Amit's lab in a project led by research students
Yonatan Katzenelenbogen, Fadi Sheban, Adam Yalin and Dr. Assaf Weiner
-- enables scientists to measure, in addition to the RNA, numerous
proteins, processes and biochemical pathways occurring inside each of
the cells. To do this, they had to develop new methods of getting inside
the cell membranes without harming its genetic content. This wealth of
"inside information" can help them draw much finer distinctions between different cell subtypes and activities than is possible with existing
methods, most of which are able to measure surface proteins only.

In fact, Amit compares those existing methods of cell characterization
with buying watermelons: They all appear identical from the outside,
even though they can taste completely different when you open them
up. Distinguishing between subtypes of cells that seem identical from
the outside, such as inhibitory- versus effector-immune cells, may be
crucial to when it comes to fighting off cancer.

Although the principal groups of immune cells had been identified many
decades ago, there are hundreds of subtypes with many different functions, which haven't been classified. "Specific immune subtypes, for example,
may play a role in promoting cancer or enabling it to evade the immune
system, provoke tissue destruction by overreacting to a virus or act
mistakenly in autoimmune syndromes, attacking our own body. Until now,
there was no sufficiently sensitive means of telling these apart from
other subtypes that appear identical from the outside," says Sheban.

In order to sort through these different immune functions inside tumors,
the Weizmann scientists used their technology to address an issue that researchers had been trying to resolve for decades: Why does the immune
system fail to recognize and kill cancer cells, and why does immunotherapy
for most tumor types often fail? In searching for an answer, they asked
whether cancers might hijack and manipulate particular immune cells
to "defend" the cancer cells from the rest of the immune system. "The
suspicion that some kind of immune cell might be actively 'collaborating'
with cancer is not as strange as it seems," explains Yalin. "Immune
responses are often meant to be short-lived, so the immune system has
its own mechanisms for shutting them down. Cancers could take advantage
of such mechanisms, enhancing the production of the 'shut-down' immune
cells, which, in turn, could prevent such immune cells as T lymphocytes
that would normally kill them from taking action." Indeed, the team
succeeded in identifying T-cell-blocking immune cells, which belonged to
a general group known as myeloid cells -- a broad group of innate immune
cells that mostly originate in the bone marrow. Although this particular
subset of suppressive myeloid cells was new, it was distinguished by
a prominent signaling receptor that Amit and his group had seen before,
called TREM2. This receptor is critical for the activity of the cells that block the actions of tumor-killing T cells; and normally cells bearing
this receptor are crucial for preventing excess tissue damage after injury
or calming an inflammatory immune response. But Amit had also come across
a version of this receptor in other immune cells involved in Alzheimer's disease, metabolic syndrome and other immune-related pathologies.

The group's next step is to develop an immunotherapy treatment using
specific antibodies that target this receptor and could prevent these immune-suppressive cells from supporting the tumor. "Because this receptor
is only expressed when there is some type of pathology," says Weiner, "targeting it will not damage healthy cells in the body." Preliminary
evidence for the TREM2 therapeutics was demonstrated by the scientists
in mouse models of cancer with genetically ablated TREM2 receptors.

In those mice, tumor-killing T cells "came back to life" and attacked
the cancer cells; and the tumors shrank significantly. If treatment
based on this finding is, in the future, proven effective for human use,
it might be administered on its own or in combination with other forms
of immunotherapy.

Yeda Research and Development, the technology transfer arm of the Weizmann Institute of Science, is currently working with Amit to develop this immunotherapy antibody for clinical use and there has already been a
great deal of interest in INs-seq technology. "Clarifying the mechanisms
of autoimmune and neurodegenerative diseases, and answering the question
of why the immune system often fails in its fight against cancer or why
most patient do not respond to existing immunotherapy -- all of these
may come down to specific actions of subsets of immune cells. We believe INs-seq may help researchers identify those particular cells and develop
new therapies to treat them," says Katzenelenbogen.


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


========================================================================== Journal Reference:
1. Yonatan Katzenelenbogen, Fadi Sheban, Adam Yalin, Ido Yofe, Dmitry
Svetlichnyy, Diego Adhemar Jaitin, Chamutal Bornstein, Adi Moshe,
Hadas Keren-Shaul, Merav Cohen, Shuang-Yin Wang, Baoguo Li, Eyal
David, Tomer- Meir Salame, Assaf Weiner, Ido Amit. Coupled scRNA-Seq
and Intracellular Protein Activity Reveal an Immunosuppressive
Role of TREM2 in Cancer.

Cell, 2020; DOI: 10.1016/j.cell.2020.06.032 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200812115328.htm

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