‘Cell-squeezing’ expands options for immunotherapy vaccines

28 May

Using microfluidic technology, scientists have developed a way to squeeze immune system B cells so their

membranes develop temporary holes, allowing the insertion of antigens that program specific immune


cells-squeezing device
As cells squeeze through the narrowing channels, small temporary holes open in their membranes, allowing target antigens to enter before they close again.
Image credit: SQZ Biotech

The technique promises to open new ways to realize the dream of immunotherapy – using patients’ own immune

systems to fight disease. So far, the idea has proved hard to translate from lab

to clinic.

The researchers – from Massachusetts Institute of Technology (MIT) in Cambridge, MA – describe their work in

a paper published in the journal PLOS ONE.

There, they explain how their approach uses B cells to create “antigen-presenting cell vaccines” that could

train a patient’s immune system to fight disease.

An antigen – short for antibody generator – is any material that triggers an attack from the immune system.

This includes, for example, a protein from a disease-causing bacterium, or a piece of a virus particle.

Previous cell vaccine studies have tended to focus on dendritic cells as antigen-presenters. Dendritic cells

are versatile scouting cells that go around sampling and processing antigens and displaying the results on their

cell surfaces.

They travel to lymph nodes and the spleen, where they meet up with killer T cells that then use the presented

antigens to help them target and destroy the invading pathogens or cancer cells.

But the MIT team says there are drawbacks to using dendritic cells for cell-based vaccines. They have a short

lifespan, they do not divide once they are activated, and they are relatively sparse in the bloodstream.

The researchers were attracted to the idea of using B cells because they can proliferate when activated and

they are abundant in the bloodstream. But they are limited, in that unlike dendritic cells, they do not

constantly sample antigens – they are genetically programmed to process only antigens that match the receptor on

their cell surface.

How to get B cells to be as versatile as dendritic cells

Lead author Gregory Szeto, a postdoc at MIT’s Koch Institute for Integrative Cancer Research, explains the

challenge they faced in their study:

“We wanted to remove an important barrier in using B cells as an antigen-presenting cell population,

helping them complement or replace dendritic cells.”

The solution they describe in their paper is a mechanical one. Using a microfluidic device, they found they

could squeeze the B cells so they temporarily distort, opening their membranes just long enough to allow the

insertion of target antigens into the cells.

The device comprises tiny parallel channels etched on a microchip. The channels become progressively

narrower, and are designed to squeeze particles the size of a cell.

Using a positive pressure system, the researchers passed a suspension of B cells and target antigen through

the channels. As a cell squeezes through the narrow part of the channel, small, temporary holes open in its

membrane, allowing the target antigen to diffuse into the cell.

The antigen does not penetrate deep into the B cell, but remains trapped in the cytosol – within the

cell membrane – a result that has the same effect as presenting the target antigen.

Thus, sporting the target antigen, the B cells become cell vaccines equipped to prime the required response

from the killer T cells.

Proof of concept tested in mice

The researchers found that the squeezed and loaded B cells were as able to prime T cells as existing methods

that use antibody-coated beads.

They then inserted the squeezed B cells and antigen-specific T cells into mice and showed that the antigen-loaded B cells could expand T cells in the spleen and lymph nodes. This, in effect, proves the concept of using

B cells as a cell vaccine system, say the researchers.

The team also notes that theirs is the first method that effectively decouples antigen delivery from B-cell

activation, thereby conferring greater control over vaccine design.

Gail Bishop, a professor of microbiology at the University of Iowa Carver School of Medicine, was not involved

in the study. She says it presents a “creative new approach with considerable potential in the development of

antigen-presenting cell vaccines,” and adds:

“This new technical approach permits loading B cells effectively with virtually any antigen and

has the additional benefit of targeting the antigens to the CD8 T-cell presentation pathway, thus facilitating

the activation of the killer T cells desired in many clinical applications.”

The team now plans to refine the method to optimize distribution and function of the immune cells in the

body. They also envisage technology improvements that will result in a bedside or field-deployable device, with

the potential to offer cheaper and more effective cell-based therapies for patients.

Some of the authors declared a financial interest in SQZ Biotechnologies, the company that developed the microfluidic technology they used in the study.

Meanwhile, another MIT team concluded in a study recently described by Medical News Today that immunotherapy stands a

better chance of fighting cancer when it enlists both arms of the immune


Writing in the journal Cancer Cell, Dane Wittrup, a professor in chemical engineering, and

colleagues describe how combining attacking tumors with antibodies (which enlists the innate immune response)

with adoptive T cell therapy (part of the adaptive immune response) successfully halted a very aggressive type

of melanoma in mice.