Study highlights importance of deeply exploring immune responses to cancer

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Over the past decade, scientists have explored vaccination as a way to fight cancer. These experimental cancer vaccines are designed to stimulate the body’s own immune system to destroy a tumor, by injecting fragments of cancer proteins found on the tumor.

So far, none of these vaccines have been approved by the FDA, but some have shown promise in clinical trials to treat melanoma and certain types of lung cancer. In a new finding that could help researchers decide which proteins to include in cancer vaccines, MIT researchers have found that vaccination against certain cancer proteins can stimulate the overall response of T cells and help shrink tumors in the patient. mouse.

The research team found that vaccination against the types of proteins they identified can help awaken populations of dormant T cells that target these proteins, thereby boosting the overall immune response.

This study highlights the importance of exploring in depth the details of immune responses to cancer. We can now see that not all anti-cancer immune responses are created equal and that vaccination can elicit a potent response against a target that would otherwise have been ignored. ”

Tyler Jacks, Professor of Biology David H. Koch, Fellow of the Koch Institute for Integrative Cancer Research and lead author of the study

MIT postdoctoral fellow Megan Burger is the lead author of the new study, which appears today in Cell.

Competition of T cells

When cells start to become cancerous, they begin to produce mutated proteins that are not seen in healthy cells. These cancerous proteins, also called neo-antigens, can alert the body’s immune system that something is wrong, and the T cells that recognize these neo-antigens start destroying the cancer cells.

Eventually, these T cells undergo a phenomenon known as “T cell depletion,” which occurs when the tumor creates an immunosuppressive environment that turns off the T cells, allowing the tumor to grow unchecked.

Scientists hope cancer vaccines could help rejuvenate these T cells and help them attack tumors. In recent years, they have worked on the development of methods for identifying neo-antigens in patients’ tumors for integration into personalized cancer vaccines. Some of these vaccines have shown promise in clinical trials to treat melanoma and non-small cell lung cancer.

“These therapies work surprisingly in a subset of patients, but the vast majority still don’t respond very well,” Burger said. “A lot of the research in our lab is trying to understand why and what we can do therapeutically to get more of these patients to respond. “

Previous studies have shown that of the hundreds of neo-antigens found in most tumors, only a small number generate a T-cell response.

The new study from MIT helps to understand why. In studies of mice with lung tumors, researchers found that as T cells targeting tumors appear, subsets of T cells that target different cancer proteins compete with each other, ultimately leading to the emergence a dominant population of T cells. Once these T cells are depleted, they still remain in the environment and suppress any competing T cell populations that target different proteins present on the tumor.

However, Burger found that if she vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, she could rejuvenate these T cell populations.

“If you vaccinate against antigens that have suppressed responses, you can trigger those T cell responses,” she says. “Trying to identify these suppressed responses and target them specifically could improve patient responses to vaccine therapies.”

Shrinkage of tumors

In this study, the researchers found that they were most successful when immunizing with neoantigens that bind weakly to immune cells responsible for presenting the antigen to T cells. ‘one of these neo-antigens to vaccinate mice with lung tumors, they found that the tumors had shrunk by an average of 27%.

“T cells proliferate more, they target tumors better, and we are seeing an overall decrease in lung tumor burden in our mouse model following therapy,” says Burger.

After vaccination, the T cell population included a type of cells that have the potential to continuously fuel the response, which could allow long-term control of a tumor.

In future work, researchers hope to test therapeutic approaches that combine this vaccination strategy with anti-cancer drugs called checkpoint inhibitors, which can dampen depleted T cells, stimulating them to attack tumors. In support of this approach, the results released today also indicate that vaccination increases the number of a specific type of T cells that have been shown to respond well to checkpoint therapies.

Source:

Massachusetts Institute of Technology

Journal reference:

Burger, ML, et al. (2021) Antigen dominance hierarchies shape T cell phenotypes of the CD8 TCF1 + progenitor in tumors. Cell. doi.org/10.1016/j.cell.2021.08.020.


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