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A new way to reprogram immune cells and direct them toward anti-tumor immunity

A collaboration between four MIT groups, led by principal investigators Laura L. Kiessling, Jeremiah A. Johnson, Alex K. Shalek, and Darrell J. Irvine, in conjunction with a group at Georgia Tech led by M.G. Finn, has revealed a new strategy for enabling immune system mobilization against cancer cells. The work, which appears today in ACS Nano, produces exactly the type of anti-tumor immunity needed to function as a tumor vaccine — both prophylactically and therapeutically.

Cancer cells can look very similar to the human cells from which they are derived. In contrast, viruses, bacteria, and fungi carry carbohydrates on their surfaces that are markedly different from those of human carbohydrates. Dendritic cells — the immune system’s best antigen-presenting cells — carry proteins on their surfaces that help them recognize these atypical carbohydrates and bring those antigens inside of them. The antigens are then processed into smaller peptides and presented to the immune system for a response. Intriguingly, some of these carbohydrate proteins can also collaborate to direct immune responses. This work presents a strategy for targeting those antigens to the dendritic cells that results in a more activated, stronger immune response.

Tackling tumors’ tenacity

The researchers’ new strategy shrouds the tumor antigens with foreign carbohydrates and co-delivers them with single-stranded RNA so that the dendritic cells can be programmed to recognize the tumor antigens as a potential threat. The researchers targeted the lectin (carbohydrate-binding protein) DC-SIGN because of its ability to serve as an activator of dendritic cell immunity. They decorated a virus-like particle (a particle composed of virus proteins assembled onto a piece of RNA that is noninfectious because its internal RNA is not from the virus) with DC-binding carbohydrate derivatives. The resulting glycan-costumed virus-like particles display unique sugars; therefore, the dendritic cells recognize them as something they need to attack.

“On the surface of the dendritic cells are carbohydrate binding proteins called lectins that combine to the sugars on the surface of bacteria or viruses, and when they do that they penetrate the membrane,” explains Kiessling, the paper’s senior author. “On the cell, the DC-SIGN gets clustered upon binding the virus or bacteria and that promotes internalization. When a virus-like particle gets internalized, it starts to fall apart and releases its RNA.” The toll-like receptor (bound to RNA) and DC-SIGN (bound to the sugar decoration) can both signal to activate the immune response.

Once the dendritic cells have sounded the alarm of a foreign invasion, a robust immune response is triggered that is significantly stronger than the immune response that would be expected with a typical untargeted vaccine. When an antigen is encountered by the dendritic cells, they send signals to T cells, the next cell in the immune system, to give different responses depending on what pathways have been activated in the dendritic cells.

Advancing cancer vaccine development

The activity of a potential vaccine developed in line with this new research is twofold. First, the vaccine glycan coat binds to lectins, providing a primary signal. Then, binding to toll-like receptors elicits potent immune activation.

The Kiessling, Finn, and Johnson groups had previously identified a synthetic DC-SIGN binding group that directed cellular immune responses when used to decorate virus-like particles. But it was unclear whether this method could be utilized as an anticancer vaccine. Collaboration between researchers in the labs at MIT and Georgia Tech demonstrated that in fact, it could.

Valerie Lensch, a chemistry PhD student from MIT’s Program in Polymers and Soft Matter and a joint member of the Kiessling and Johnson labs, took the preexisting strategy and tested it as an anticancer vaccine, learning a great deal about immunology in order to do so.

“We have developed a modular vaccine platform designed to drive antigen-specific cellular immune responses,” says Lensch. “This platform is not only pivotal in the fight against cancer, but also offers significant potential for combating challenging intracellular pathogens, including malaria parasites, HIV, and Mycobacterium tuberculosis. This technology holds promise for tackling a range of diseases where vaccine development has been particularly challenging.”

Lensch and her fellow researchers conducted in vitro experiments with extensive iterations of these glycan-costumed virus-like particles before identifying a design that demonstrated potential for success. Once that was achieved, the researchers were able to move on to an in vivo model, an exciting milestone for their research.

Adele Gabba, a postdoc in the Kiessling Lab, conducted the in vivo experiments with Lensch, and Robert Hincapie, who conducted his PhD studies with Professor M.G. Finn at Georgia Tech, built and decorated the virus-like particles with a series of glycans that were sent to him from the researchers at MIT.

“We are discovering that carbohydrates act like a language that cells use to communicate and direct the immune system,” says Gabba. “It’s thrilling that we have begun to decode this language and can now harness it to reshape immune responses.”

“The design principles behind this vaccine are rooted in extensive fundamental research conducted by previous graduate student and postdoctoral researchers over many years, focusing on optimizing lectin engagement and understanding the roles of lectins in immunity,” says Lensch. “It has been exciting to witness the translation of these concepts into therapeutic platforms across various applications.”

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Protecting the rights of internet users, in Mexico and worldwide

After the Arab Spring and the Occupy movement, a single Tweet or Facebook post was able to mobilize thousands in a matter of hours. In 2012, protests came to the streets of Mexico as young people demonstrated against the results of the general election.

A recent college graduate of the National Autonomous University of Mexico, Mariel García-Montes had classmates who were nonviolently participating in the protests. One was arrested and jailed, and as García-Montes pored over online surveillance videos and photos to help free her, she was struck by the power of the tools at her disposal.

“Videos and maps and photographs placed her at a different location at the time that her arraignment said,” García-Montes says. “When she was able to walk out of jail partly because of technological evidence, I thought, ‘Maybe this is a window of opportunity to use technology for social good.’”

Over a decade later, García-Montes is still looking for more of those windows. She first came to MIT in 2016 to pursue a master’s degree in comparative media studies and is currently working with Professor Eden Medina on a PhD thesis in the Program in Science, Technology, and Society, which will chart the history of technology’s influence on surveillance and privacy, particularly in her home country.

“I would love for my work, theoretical and practical, to build into these global movements for necessary and proportionate surveillance,” she says. “It needs to have counterweights and limits, and it needs to be really thought through to preserve people’s privacy and other rights, not just security.”

“More broadly,” she continues, “I would love to be part of a generation thinking about what technology would look like if we put the public interest first.”

Growing up alongside the internet

García-Montes has been thinking about justice and the public for much of her life, thanks in large part to her mother, who taught philosophy at the university level.

“She was the ultimate professor for me,” she says. “She provided me with a moral compass and intellectual curiosity, and I’m grateful I get to live her dreams.”

Her mother was also instrumental in piquing her interest in the internet. As a professor, she had access to the internet at a time when few Mexicans did, and set García-Montes up with an email account and allowed her to use the computer at the university when she was a child. The experience was formative, as she noticed the “vast difference” between those who had access and those who did not. For example, she recalls learning online about a devastating tsunami in Asia, while none of her peers had any idea that it was happening.

As time passed and more and more people did gain internet access, the online landscape changed, particularly for young people. García-Montes quickly realized that someone needed to take responsibility for keeping those young people safe and internet-literate, and she worked with a number of organizations that did just that, such as UNICEF and Global Changemakers. The issues have only compounded since then, but she isn’t letting up either.

“There’s no silver bullet,” she says. “We need to rethink the entire ecosystem. We cannot put it on parents to teach their kids. We cannot put it on teachers. We cannot put it on online users. Instead of only centering profit and only centering page views or engagement, we need to also center pro-social behavior and the public interest.”

Raised by women — her mom, her aunt, her cousin, and her grandmother — García-Montes incorporates the feminist ideals of her upbringing into her academic work wherever she can. In 2022, she helped write a paper with MIT associate professor of urban science and planning Catherine D’Ignazio that examined the ways activists around the world are trying to address the deficiencies in government data on gender-related violence against women. The data are often absent or incomplete, so she and her co-authors highlighted the vital work being done to fill in the gaps.

“​​When Catherine started to work with feminicide data activists, I knew a bunch of them because I had worked with them previously,” she says. “I thought, ‘Oh, my goodness, the day has finally come that these people can have the prominence that they’ve long deserved.’ The hours of work that they put in and the emotional toll it takes on them is just outstanding, and they weren’t really getting the recognition for that labor and their technical expertise.”

Her dissertation is a study of the history of surveillance technologies in Mexico. Specifically, she is looking at the ways contemporary debates on information technologies, such as spyware and facial recognition, interact with existing governance and infrastructures.

The future of privacy and community

Her thesis research has instilled in García-Montes a deep concern for where things are headed for the average citizen.

“Different types of data collection continue to be developed because of the data broker industry,” she says. “Your power bill can be an instrument of surveillance, and facial recognition has been appearing in airports. The forms of data collection are becoming much more nuanced, much more pervasive, and much harder to evade.”

This pervasiveness has led to a general acceptance among the population, she says, but she’s also encouraged by the advocacy groups that have continued to fight on. She agrees with those groups that it should not be left to individuals to protect their own data, and that ultimately, there needs to be a legislative and cultural environment that values the preservation of privacy.

“The awareness of fights that have been won is rising,” she says. “The awareness of the loss of privacy is also rising, and so I don’t think that it’s going to be a clear win for privacy-violating companies.”

While her studies at MIT fill most of her time, García-Montes also finds purpose participating in community life in her Greater-Boston neighborhood. During the coronavirus pandemic, García-Montes and her neighbors forged bonds as they provided mutual aid for the essential workers and vulnerable people of their neighborhood. The camaraderie they developed persists today.

Whether online or in real life, “There is joy in community,” she says. “At the root of it, I want to be around people. I want to know my neighbors, and being able to use technology to solve some of our mutual aid needs helps me feel good.”