In addition to surveilling the body for external threats, the immune system also seeks out and eliminates cells that have gone cancerous or are precancerous. Nonetheless, some cancer cells manage to dodge this detection and proliferate into tumors.
Once they settle, tumor cells frequently emit immunosuppressive signals, causing T cells to become “exhausted” and incapable of attacking the tumor. In recent times, certain cancer immunotherapy medications have demonstrated significant success in revitalizing these T cells so they can recommence their assault on tumors.
Although this method has proven effective against cancers like melanoma, it does not perform as effectively for others, such as lung and ovarian cancer. MIT Associate Professor Stefani Spranger is investigating how these tumors manage to suppress immune responses, hoping to discover novel methods to invigorate T cells to attack them.
“We genuinely want to grasp why our immune system fails to recognize cancer,” Spranger states. “And I’m particularly excited about tackling the more challenging cancers because I believe that’s where we can achieve the most substantial advancements.”
Her research has resulted in a deeper understanding of the elements that influence T-cell responses to tumors and has raised the prospect of enhancing those responses through vaccination or therapy with immune-boosting substances known as cytokines.
“We’re focused on identifying what the precise issue is, and then teaming up with engineers to devise an effective solution,” she remarks.
Revitalizing T cells
As a student in Germany, where scholars often have to select their academic major while still in secondary school, Spranger envisioned a career in the pharmaceutical sector and chose to major in biology. At Ludwig Maximilian University in Munich, her studies commenced with traditional biology topics like botany and zoology, leading her to question her choice. However, upon taking courses in cell biology and immunology, her passion reignited, and she advanced into a biology graduate program at the university.
During a paper discussion course early in her graduate studies, Spranger was tasked with reviewing a Science article on a promising new immunotherapy for melanoma. This approach involves isolating tumor-infiltrating T-cells during surgery, expanding them in number, and then returning them to the patient. For over 50 percent of those patients, the tumors were completely eradicated.
“To me, that was revolutionary,” Spranger recollects. “You can utilize the patient’s own immune system, make minimal alterations, and then the cancer vanishes.”
Spranger completed her PhD in a lab that focused on further enhancing that method, known as adoptive T-cell transfer therapy. At that time, she was still inclined towards a career in pharmaceuticals, but after earning her PhD in 2011, her husband, also a biologist, persuaded her that they should both pursue postdoctoral positions in the U.S.
They found themselves at the University of Chicago, where Spranger operated in a lab investigating how the immune system reacts to tumors. There, she found that while melanoma typically responds well to immunotherapy, a small subset of melanoma patients has T cells that do not respond to the therapy at all. This piqued her interest in uncovering why the immune system does not always react appropriately to cancer, and in discovering methods to stimulate it.
During her postdoctoral fellowship, Spranger also realized that she cherished mentoring students, a role she hadn’t experienced while a graduate student in Germany. This experience steered her away from the pharmaceutical arena, directing her towards an academic career.
“I had my first mentoring experience with an undergraduate in the lab, and observing that individual grow as a scientist, evolving from hardly asking questions to conducting full experiments and formulating hypotheses, transformed my approach to science and shaped my vision of what academia should represent,” she remarks.
Simulating the immune system
When applying for faculty positions, Spranger was attracted to MIT due to its collaborative atmosphere and its Koch Institute for Integrative Cancer Research, which presented opportunities to work alongside a large network of engineers involved in immunology.
“That community is extremely dynamic, and it’s wonderful to be part of it,” she states.
Building on the research she conducted during her postdoc, Spranger sought to investigate why certain tumors effectively respond to immunotherapy while others do not. For many of her initial studies, she employed a mouse model of non-small-cell lung cancer. In human patients, most of these tumors do not react positively to immunotherapy.
“We create model systems that mimic each of the distinct subsets of non-responsive non-small cell lung cancer, and we’re delving deep into the mechanism of why the immune system fails to respond appropriately,” she says.
As part of this endeavor, she has examined why the immune system functions differently across various tissue types. While immunotherapy agents known as checkpoint inhibitors can elicit a strong T-cell response in the skin, they are far less effective in the lung. However, Spranger has demonstrated that T cell responses in the lung can be enhanced when immune molecules called cytokines are administered alongside the checkpoint inhibitor.
These cytokines function, in part, by activating dendritic cells — a category of immune cells that facilitate the initiation of immune responses, including T cell activation.
“Dendritic cells act as the conductor for the orchestra of all T cells, even though they are a very sparse cell population,” Spranger explains. “They can communicate the type of threat they perceive from stressed cells and then guide the T cells on what actions to take and where to go.”
Spranger’s laboratory is now commencing studies on other tumor types that show no response to immunotherapy whatsoever, including ovarian cancer and glioblastoma. Both the brain and the peritoneal cavity seem to inhibit T-cell responses to tumors, and Spranger aims to determine how to overcome this immunosuppression.
“We are specifically concentrating on ovarian cancer and glioblastoma because current treatments have been ineffective for those cancers,” she states. “We aim to understand what must be done in those areas to foster a robust anti-tumor immune reaction.”