New research from investigators at MIT may help guide vaccine developers to decide which proteins to include in new vaccines against cancer.
Cancer cells display unique mutated proteins called neoantigens on their surfaces. Fragments of certain neoantigens when injected into the body can stimulate the body’s immune system to annihilate the tumor, acting like a vaccine. Such cancer vaccines have not yet gained FDA approval, but vaccines against melanoma and non-small cell lung cancer show promise.
In the new study, the MIT researchers reveal vaccinating against certain neoantigens can boost overall T-cell response by reawakening dormant T cell populations that target those proteins and help shrink tumors in mice.
“This study highlights the importance of exploring the details of immune responses against cancer deeply. We can now see that not all anticancer immune responses are created equal and that vaccination can unleash a potent response against a target that was otherwise effectively ignored,” said Tyler Jacks, PhD, the David H. Koch professor of biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.
Megan Burger, PhD, postdoctoral fellow at MIT, is the lead author of the new study, which appears in the Cell article titled, “Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors.”
Tumors create an immunosuppressive environment around them. This creates T-cell exhaustion, which disables populations of T cells, allowing the tumor to grow unchecked. Cancer vaccines could rejuvenate disabled T cells enabling them to attack tumors.
Computational approaches have helped identify therapeutically actionable neoantigens in patient tumors for incorporation into personalized cancer vaccines. “These therapies work amazingly in a subset of patients, but the vast majority still don’t respond very well,” said Burger. “A lot of the research in our lab is aimed at trying to understand why that is and what we can do therapeutically to get more of those patients responding.”
Although numerous neoantigens are found in most tumors, only a small number mount a T-cell response, earlier studies show. The new study helps explain the reason behind this.
The researchers observed, as tumor-targeting T cells arise in mice with lung tumors, subsets of T cells that target different cancerous proteins compete, leading to the emergence of one dominant population of T cells. Even when this dominant set of T cells no longer attacks tumor cells, it remains near the tumor and suppresses competing T cell populations that target different proteins found on the tumor.
When the team vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, they observed that the suppressed T cell populations rejuvenated. “If you vaccinate against antigens that have suppressed responses, you can unleash those T-cell responses,” Berger said. “Trying to identify these suppressed responses and specifically targeting them might improve patient responses to vaccine therapies.”
The researchers observed that they were most successful in shrinking the tumors in mice with lung tumors when they were vaccinated with neoantigens that bound weakly to immune cells that present the antigen to the T cells. “The T cells proliferate more, they target the tumors better, and we see an overall decrease in lung tumor burden in our mouse model as a result of the therapy,” Burger said.
Upon vaccinating mice with such suppressed neoantigens, the T cell population included a type of cell that can continuously refuel the response allowing long-term control of a tumor, the authors noted.
The study took a close look at the interplay of different populations of T cells marked by the transmembrane protein CD8, and how this interplay affects the function of the different T cell populations and their ability to control tumors.
In mouse lung adenocarcinoma, immune dominance and rapid expansion are established in tumors by that population of CD8 T cells where the neoantigen most stably binds the major histocompatibility complex (MHC)—a protein complex that acts as a molecular billboard to display foreign proteins so that compatible proteins on immune system cells can identify them.
The authors showed T cells that respond to subdominant neoantigens express TCF1—a transcription factor that plays an important role in T cell development and differentiation—and respond to a prominent cancer therapy called immune checkpoint blockade (ICB) therapy.
The researchers analyzed human samples and sequencing datasets to show that T cells marked by CCR6 and TCF1 exist across human cancers and do not respond to immune checkpoint blockade. Vaccination eliminates this class of T cells, significantly improving the subdominant response. This highlights a potential strategy to successfully engage many simultaneous neoantigen responses against tumors.
In their next experiments, the researchers intend to test therapeutic approaches combining this vaccination strategy with checkpoint inhibitors, which can induce exhausted T cells to divide again and attack tumors. The current findings indicate that vaccination boosts the division of T cells expressing CCR6 and TCF1 that respond well to checkpoint therapies.