New approach to nongenetic T-cell-based immunotherapy
© Wiley-VCH, re-use with credit to 'Angewandte Chemie' and a link to the original article.
Immunotherapies for cancer aim to induce the immune system
to combat cancer cells more effectively. In the journal Angewandte
Chemie, a Chinese research team has now described a new, modular
strategy for T-cell-based immunotherapy that manages to work without
complex genetic modifications. Modulation of cell-cell communications
through an ingenious regulatory circuit using various small, specially
folded DNA molecules (aptamers) causes cancer cells to directly activate
their mortal enemies, T cells.
For multicell organisms like our bodies to function
correctly, the cells must “coordinate” with each other. In this complex
communications network, signals are sent and received, processed, and
passed on. The regulation of specific membrane receptors that bind to
signal molecules plays an important role in this process. In a typical
example, components of the immune system, known as antigen-presenting
cells (APCs), sense the presence of cancer antigens. They transmit the
signal to lymph nodes, in which specific T cells are activated by their
receptors, move into the bloodstream, and kill the cancer cells.
Unfortunately, cancer cells use a variety of “loopholes” to escape the
immune system.
The team at Hunan University, Hangzhou Institute of
Medicine, the Chinese Academy of Sciences, and Shanghai Jiao Tong
University is working on ways to close these loopholes. Their goal is to
establish new cellular interactions without having to produce
genetically modified immune cells or receptors. The idea is to produce a
“short circuit” in the communication pathways, by which the T cells are
activated directly by the tumor cells, avoiding the detour through APCs.
Led by Weihong Tan and Liping Qiu, the team developed a
“regulatory circuit” consisting of two modules: 1)
“recognition-then-triggering” and 2) “aggregation-then-activation”. The
circuit is based on different DNA aptamers – short DNA segments that
fold into a “preprogrammed” 3D structure and “recognize” specific target
molecules.
The DNA for module 1) is initially inactive and partially
paired into a double strand. If cancer cells are present, the aptamer
portion of the “recognition” single strand binds to protein tyrosinase
kinase 7, a protein found in large numbers on the surface of many cancer
cells. This splits the DNA double strand, releasing the “triggering
strand”, which triggers module 2).
Module 2) requires two more types of aptamer. Both
specifically bind to CD28 immunoreceptors on the surfaces of T cells.
CD28 is a co-stimulator in the activation of T cells. This triggering
strand binds to an additional “loop” on a type 1 aptamer. The loop opens
and the newly released end binds to a type 2 aptamer, which then binds
another type 1 aptamer, and so on (hybridization). This results in a
double strand and the bound CD28 receptors aggregate, triggering a
signal cascade that massively amplifies the activation of T cells. In
this way, “short-circuited” cell communication causes cancer cells to
very effectively directly induce T cells to kill them.
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About the Author
Dr. Liping Qiu is the Professor of Hunan University and
Hangzhou Institute of Medicine, the Chinese Academy of Sciences. She has
been actively involved in interdisciplinary research of Analytical
Chemistry and Biomedicine. Her research focuses on functional nucleic
acids and their applications in biosensing, bioimaging, and cell-based
immunity.
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