Bacteria may aid anti-cancer immune response
The findings of a new study may explain the microbiome-immunotherapy connection

Date:
March 22, 2021
Source:
Weizmann Institute of Science
Summary:
Cancer immunotherapy may get a boost from an unexpected direction:
bacteria residing within tumor cells. Researchers have discovered
that the immune system "sees" these bacteria and shown they can
be harnessed to provoke an immune reaction against the tumor. The
study may also help clarify the connection between immunotherapy
and the gut microbiome, explaining the findings of previous research
that the microbiome affects the success of immunotherapy.



FULL STORY ========================================================================== Cancer immunotherapy may get a boost from an unexpected direction:
bacteria residing within tumor cells. In a new study published in Nature, researchers at the Weizmann Institute of Science and their collaborators
have discovered that the immune system "sees" these bacteria and shown
they can be harnessed to provoke an immune reaction against the tumor. The study may also help clarify the connection between immunotherapy and
the gut microbiome, explaining the findings of previous research that
the microbiome affects the success of immunotherapy.


========================================================================== Immunotherapy treatments of the past decade or so have dramatically
improved recovery rates from certain cancers, particularly malignant
melanoma; but in melanoma, they still work in only about 40% of the
cases. Prof. Yardena Samuels of Weizmann's Molecular Cell Biology
Department studies molecular "signposts" - - protein fragments, or
peptides, on the cell surface -- that mark cancer cells as foreign and
may therefore serve as potential added targets for immunotherapy. In
the new study, she and colleagues extended their search for new cancer signposts to those bacteria known to colonize tumors.

Using methods developed by departmental colleague Dr. Ravid Straussman,
who was one of the first to reveal the nature of the bacterial "guests"
in cancer cells, Samuels and her team, led by Dr. Shelly Kalaora and
Adi Nagler (joint co-first authors), analyzed tissue samples from 17
metastatic melanoma tumors derived from nine patients. They obtained
bacterial genomic profiles of these tumors and then applied an approach
known as HLA-peptidomics to identify tumor peptides that can be recognized
by the immune system.

The research was conducted in collaboration with Dr. Jennifer A. Wargo
of the University of Texas MD Anderson Cancer Center, Houston, Texas;
Prof Scott N.

Peterson of Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Prof Eytan Ruppin of the National Cancer Institute, USA;
Prof Arie Admon of the Technion -- Israel Institute of Technology and
other scientists.

The HLA peptidomics analysis revealed nearly 300 peptides from 41
different bacteria on the surface of the melanoma cells. The crucial
new finding was that the peptides were displayed on the cancer cell
surfaces by HLA protein complexes -- complexes that are present on the membranes of all cells in our body and play a role in regulating the
immune response. One of the HLA's jobs is to sound an alarm about anything that's foreign by "presenting" foreign peptides to the immune system so
that immune T cells can "see" them. "Using HLA peptidomics, we were able
to reveal the HLA-presented peptides of the tumor in an unbiased manner," Kalaora says. "This method has already enabled us in the past to identify
tumor antigens that have shown promising results in clinical trials."
It's unclear why cancer cells should perform a seemingly suicidal act
of this sort: presenting bacterial peptides to the immune system, which
can respond by destroying these cells. But whatever the reason, the fact
that malignant cells do display these peptides in such a manner reveals an entirely new type of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut
microbiome affects immunotherapy. Some of the bacteria the team identified
were known gut microbes. The presentation of the bacterial peptides
on the surface of tumor cells is likely to play a role in the immune
response, and future studies may establish which bacterial peptides
enhance that immune response, enabling physicians to predict the success
of immunotherapy and to tailor a personalized treatment accordingly.

Moreover, the fact that bacterial peptides on tumor cells are visible to
the immune system can be exploited for enhancing immunotherapy. "Many of
these peptides were shared by different metastases from the same patient
or by tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to produce immune activation," Nagler says.

In a series of continuing experiments, Samuels and colleagues incubated T
cells from melanoma patients in a laboratory dish together with bacterial peptides derived from tumor cells of the same patient. The result:
T cells were activated specifically toward the bacterial peptides.

"Our findings suggest that bacterial peptides presented on tumor
cells can serve as potential targets for immunotherapy," Samuels
said. "They may be exploited to help immune T cells recognize
the tumor with greater precision, so that these cells can mount
a better attack against the cancer. This approach can in the
future be used in combination with existing immunotherapy drugs." ========================================================================== Story Source: Materials provided by Weizmann_Institute_of_Science. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Shelly Kalaora, Adi Nagler, Deborah Nejman, Michal Alon, Chaya
Barbolin,
Eilon Barnea, Steven L. C. Ketelaars, Kuoyuan Cheng, Kevin Vervier,
Noam Shental, Yuval Bussi, Ron Rotkopf, Ronen Levy, Gil Benedek,
Sophie Trabish, Tali Dadosh, Smadar Levin-Zaidman, Leore T. Geller,
Kun Wang, Polina Greenberg, Gal Yagel, Aviyah Peri, Garold Fuks,
Neerupma Bhardwaj, Alexandre Reuben, Leandro Hermida, Sarah
B. Johnson, Jessica R. Galloway- Pen~a, William C. Shropshire,
Chantale Bernatchez, Cara Haymaker, Reetakshi Arora, Lior Roitman,
Raya Eilam, Adina Weinberger, Maya Lotan- Pompan, Michal Lotem,
Arie Admon, Yishai Levin, Trevor D. Lawley, David J. Adams, Mitchell
P. Levesque, Michal J. Besser, Jacob Schachter, Ofra Golani, Eran
Segal, Naama Geva-Zatorsky, Eytan Ruppin, Pia Kvistborg, Scott
N. Peterson, Jennifer A. Wargo, Ravid Straussman, Yardena Samuels.

Identification of bacteria-derived HLA-bound peptides in melanoma.

Nature, 2021; DOI: 10.1038/s41586-021-03368-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/03/210322085517.htm

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