Pushing past pancreatic tumors' defenses
Date:
February 16, 2022
Source:
Cold Spring Harbor Laboratory
Summary:
Researchers found that some cancer cells weave a deactivating
signal into a protective coat of armor, immobilizing and excluding
T cells that would otherwise kill them. This immune deactivation
pathway offers a promising new therapeutic approach for pancreatic,
breast, and colorectal cancers.
FULL STORY ==========================================================================
Our immune systems have the potential to find and destroy cancer
cells. But cancer cells can be clever and develop tricks to evade the
immune system. Cold Spring Harbor Laboratory Professor Douglas Fearon and
his former postdoc ZhiKai Wang found one such trick. Cancer cells weave
a deactivating signal into a protective coat of armor that excludes T
cells that would otherwise kill them.
This immune deactivation pathway offers a promising new therapeutic
approach for pancreatic, breast, and colorectal cancers.
==========================================================================
T cells patrol the body looking for cancers and pathogens. If they and/or
their immune system teammates find an intruder, the T cells are mobilized
to attack.
Wang, currently a research fellow at the University of Science and
Technology of China in Hefei, discovered this mobilization was disabled
by a combination of three proteins woven into a protective coating
surrounding cancer cells: a signal that usually attracts T cells called
CXCL12, a filament called KRT19, and a protein that fuses the former
proteins together called TGM2.
The scientists used genetic editing to turn off the production of KRT19
or TGM2 in mouse pancreatic tumors. Without KRT19 or TGM2, the cancer
cells lost the CXCL12-KRT19 protection and T cells were able to infiltrate
and attack. The pancreatic tumors shrank or disappeared.
Why did this coat of proteins repel T cells from the tumors? Wang says,
"It is kind of counterintuitive because CXCL12 is a chemokine (chemical attractant) that attracts immune cells. But we found that CXCL12 is
in an unusually high concentration on the surface of the cancer cells,
where it does the opposite by making T cells immobile." CXCL12 usually
does its work as a single protein. But at high concentrations on the
surface of cancer cells, the protein is in a complex with KRT19 and
forms a branch-like network. T cell movement was reduced dramatically
by this network.
The study was published in the Proceedings of the National Academies
of Sciences. In a previous small clinical study of pancreatic cancer
patients, Fearon and collaborators showed that the drug plerixafor
(a CXCL12 receptor blocker) increased the infiltration of T cells into patients' pancreatic tumor tissues. The current study now shows why this immunotherapeutic effect occurs.
Fearon and Wang hope CXCL12 and KRT19 will provide new therapeutic targets
that boost the immune system's chances of killing off cancer cells.
========================================================================== Story Source: Materials provided by
Cold_Spring_Harbor_Laboratory. Original written by Luis Sandoval. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Zhikai Wang, Philip Moresco, Ran Yan, Jiayun Li, Ya Gao, Daniele
Biasci,
Min Yao, Jordan Pearson, Jaclyn F. Hechtman, Tobias Janowitz,
Raza M.
Zaidi, Matthew J. Weiss, Douglas T. Fearon. Carcinomas assemble
a filamentous CXCL12-keratin-19 coating that suppresses T
cell-mediated immune attack. Proceedings of the National Academy
of Sciences, 2022; 119 (4): e2119463119 DOI: 10.1073/pnas.2119463119 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220216083000.htm
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