Researchers identify new targets for immunotherapy in colon cancer


Date:
March 31, 2022
Source:
Technische Universita"t Dresden
Summary:
Scientists identify a pathway of immune cell inhibition that
may provide the basis for novel approaches to immunotherapy of
colon cancer. Their results also highlight important roles of the
intestinal microbiota in the development of the disease.



FULL STORY ========================================================================== Colon cancer is one of the most common types of cancer. Particularly
in advanced stages of disease, the treatment still largely relies on traditional chemotherapy. The new generation of cancer treatments,
so-called immunotherapies, has only been effective in a small subgroup
of colon cancers.

TU Dresden scientists led by Prof. Sebastian Zeissig have now identified proteins that are promising targets for new immunotherapies against
colon cancer. Their results also underline the central role of intestinal bacteria in the development of colon cancer. The study was published in
the journalImmunityon March 31, 2022.


==========================================================================
Our bodies can naturally clear cancerous cells. Every day our immune
system may detect mutated cells in our bodies and destroy them. Once in
a while though, cancerous cells can find a way to hide from the immune
system. The cells develop molecular signals that block immune cells from recognizing them as a threat. This, among other strategies, allows cancer
cells to multiply and grow into tumors. Understanding the molecular
mechanism of this process allowed for the development of new cancer
treatments, the so-called immunotherapies. These treatments can unleash
the patient's immune system to target the tumor and limit its growth.

Unfortunately, current immunotherapies are not effective for all types of cancers. Most cases of colon cancer, one of the most commonly diagnosed
type of cancer, do not respond to these treatments. Now, a team of
researchers from TU Dresden described a new pathway that lets colon
cancer hide from the immune system. Their results provide a potential
first step towards the development of a new generation of immunotherapies.

How Colon Cancer Hides from the Immune System Inhibition of immune
cells is carried out by special signals present on the surface of
cancer cells. "These signals are known as checkpoint proteins," says
Prof. Sebastian Zeissig from the University Hospital Dresden and the
Center for Regenerative Therapies Dresden (CRTD) at TU Dresden who led
the research team.

Current immunotherapies use drugs called checkpoint inhibitors to target
a small set of known checkpoint proteins. Unfortunately, this approach
had only a very limited impact on colon cancer growth. "This raised
the question of whether there are other checkpoint proteins that may
represent more promising targets for immunotherapy in colon cancer,"
says Dr. Kenneth Peuker, author of the study.

Researchers analyzed colon cancer samples and looked for signal proteins present in tumor cells but not in the healthy tissue. Two proteins caught
their attention. CB7H3 and B7H4 were present in large number in colon
cancer cells while almost undetectable in the healthy tissue.



==========================================================================
"We decided to block B7H3 and B7H4 in colon cancer cells," says
Dr. Peuker.

"The result was startling. Tumor tissue in which these signals were
disabled showed significantly slowed growth or even shrinking. We have
observed that now the immune cells could invade the cancer tissue and
started to control tumor cells." Additional tests confirmed that the B7H3
and B7H4 proteins are indeed working as checkpoint proteins. "Blocking
these signals suddenly allowed immune system to attack tumor cells,"
adds Prof. Zeissig.

Scientists found B7H3 and B7H4 to be present not only in the primary
colon cancer tumors but also in their metastases in the liver. Turning
these proteins off slowed the growth of the primary tumors but also
their liver metastases.

The team observed that some of the treated mice survived long-term
despite having metastatic tumors.

Runaway Bacteria Block Immune Responses The team characterized a broad
cascade of events that allows colon cancer to develop its ability to block immune cells. They were able to show that breaking the intestinal barrier
is a crucial step in the process. When the intestinal barrier breaks at
sites of tumor development, bacteria that are normally present in the
intestine can suddenly enter the surrounding tissue. This is considered
an important early event in the development of colon cancer. Now,
Prof. Zeissig's team could show that these bacterial runaways serve as an initial trigger for the colon cancer cells to hide from the immune system.

"We found that cells present in the tissue can detect the invading
bacteria.

This, in turn, activates a full cascade of steps. The resulting molecular communication between the cells eventually leads the cancer cells to
project B7H3 and B7H4 on their surface and hide from the immune system,"
says Dr.

Peuker.

The team could show that using broad-spectrum antibiotics to destroy the invading intestinal bacteria also reduced the tumor size and decreased
the extent of liver metastases. "Our results provide a new link between microbiota and tumor growth in colon cancer. We would like to focus more
on this angle in the future," says Prof. Zeissig.

A Step Closer to New Colon Cancer Immunotherapies The results of the
new study come predominantly from research in mice but offer a promising outlook for future cancer therapies for humans. "Our analyses of human
samples showed that B7H3 and B7H4 are also present in human colon cancer
cells and that their presence correlates with poorer outcomes of colon
cancer patients. These proteins are also barely detectable in healthy
tissues in humans which suggests that their targeting may be safe,"
says Prof. Zeissig.

"We hope that our work will serve as a foundation for new studies that
address the efficacy of targeting of B7H3 and B7H4 in human colon cancer
in the future," adds Prof. Zeissig.


========================================================================== Story Source: Materials provided by
Technische_Universita"t_Dresden. Original written by Magdalena
Gonciarz. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kenneth Peuker, Anne Strigli, Daniele V.F. Tauriello, Alexander
Hendricks, Witigo von Scho"nfels, Greta Burmeister, Mario
Brosch, Alexander Herrmann, Sandra Kru"ger, Jessica Nitsche, Lea
Južnić, Marc Marius Geissler, Andreas Hiergeist, Andre'
Gessner, Jakob Wirbel, Ruby Priyadarshini Ponnudurai, Antje Tunger,
Rebekka Wehner, Daniel E. Stange, Ju"rgen Weitz, Daniela E. Aust,
Gustavo B. Baretton, Marc Schmitz, Christoph Ro"cken, Jochen Hampe,
Sebastian Hinz, Georg Zeller, Triantafyllos Chavakis, Clemens
Schafmayer, Eduard Batlle, Sebastian Zeissig. Microbiota-dependent
activation of the myeloid calcineurin-NFAT pathway inhibits
B7H3- and B7H4-dependent anti-tumor immunity in colorectal
cancer. Immunity, 2022; DOI: 10.1016/ j.immuni.2022.03.008 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220331121238.htm

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