Introducing STING into Cancer Immunotherapy | Massachusetts Institute of Technology News

Immune checkpoint blockade therapy has been revolutionary in the treatment of some types of cancer and has emerged as one of the most promising treatments for diseases such as melanoma, colon cancer and non-small cell lung cancer. .

In some cases, checkpoint inhibitor therapy induces a strong immune response that clears the tumor, but checkpoint inhibitors are not effective in all tumor types or in all patients. In addition, some patients who experience the initial benefits of these treatments have their cancer come back. Only a small minority of patients treated with checkpoint inhibition therapy have a durable effect. Researchers are developing a variety of combination therapeutic strategies to overcome resistance to checkpoint inhibitor therapy, with the STING pathway emerging as one of the most attractive research areas.

In a study published in Advanced healthcare materialsA team of researchers at MIT has developed a therapeutic cancer vaccine that can restore STING signaling and eliminate most tumors in mouse models of colon cancer and melanoma with minimal side effects. This vaccine also suppressed metastasis in a breast cancer mouse model and prevented tumor recurrence in cured mice.

“We have repurposed a naturally occurring adapter protein into a novel bifunctional cancer vaccine that initiates and maintains effective anti-tumor immunity. This protein complex stimulates a potent immune attack. and helped form long-term memory for tumors in mouse models of colon cancer and melanoma,” said Angela Belcher, senior author of the study and member of the Koch Institute for Integrative Cancer Research. I’m here. Head of MIT Biotechnology.

The research was led by MIT postdoc Yangpu He, in collaboration with the lab of Paula Hammond, a member of the Koch Institute, professor at MIT Lab, and dean of chemical engineering at MIT. was done. Other authors on this paper include Celestine Hon, Shengnan Huang, Justin Kaskow, Gil Covarrubias, Ivan Pires, and James Sacane.

Components of vaccines

Immune checkpoints are an important part of the system that helps the immune system distinguish between the body’s own healthy cells and threats such as harmful bacteria and cancer cells. When a checkpoint protein on the surface of an immune cell binds to a partner protein on another cell, the interaction generates a signal that prevents her T cells and other immune cells from mounting an attack. By presenting the same kind of partner protein, cancer cells can avoid destruction by the immune system. Immune checkpoint blockade therapy, whose discovery was recognized by his 2018 Nobel Prize in Physiology or Medicine, works by binding to partner proteins on cancer cells, allowing the immune system to respond. increase.

The STING pathway plays an important role in enhancing immune responses against pathogens and cancer cells, and is therefore a promising partner for immune checkpoint inhibition therapy. This pathway is also known to influence the immune system in other ways, such as maturation, specialization and activation of specific types of immune cells.

Several clinical trials combining immune checkpoint blockade and STING-targeted therapy are underway, but few have been approved by the US Food and Drug Administration. The main reason is that systemic administration can cause severe toxic and inflammatory side effects. Direct injection of STING into the tumor can reduce side effects, but this strategy still leaves one major unsolved problem. That means 19 percent of people carry a variant of his STING gene and do not respond to STING targeted therapy.

In previous studies, researchers have attempted to address this challenge by engineering protein complexes that can restore STING signaling in cell lines that lack the STING protein or have mutated and disabled genes. did it. This complex combines a portion of the STING protein responsible for triggering downstream signaling with cGAMP, a small molecule that stimulates the STING pathway.

In the current study, the researchers added another component to the STING-cGAMP complex. It is the smaller forms of antibodies known as nanobodies that carry immune checkpoint inhibition therapy.

After direct injection into tumors, cancer vaccines eliminated 70-100% of tumors in mouse models of colon cancer and melanoma. The researchers found that the majority of the vaccine remained within the tumor and minimal weight loss in treated mice, suggesting a low risk of systemic side effects. Cured mice were tumor-free after six months of observation, but when the researchers rechallenged the mice with tumor cells to simulate a recurrence of the cancer, 100 percent of those mice were immune. Rejected tumor cells by memory. When treated in mice with the STING gene inactivated, the vaccine still restored STING signaling and significantly reduced tumor size, although it was not as effective as in mice with normal STING function.

“With further development, this platform not only promises to enhance the efficacy and prevent recurrence of checkpoint blockade therapy in a wider range of cancer patients, but also makes checkpoint blockade therapy viable in large populations. It could lead to new cancer treatments that are more effective,” says Professor Belcher. Loss-of-function He Percentage of the population with the STING mutation. ”

The Surprising Role of CD4+ T Cells

When researchers investigated the mechanisms of tumor response to vaccines, they unexpectedly found that a subtype of T cells called CD4+ T cells plays a pivotal role in the development of anti-tumor immunity.

In clinical cancer therapy, CD4+ T cells play multiple roles in the immune system and are usually associated with immunosuppression. Since then, most research on checkpoint blockade therapy and the STING pathway has focused on other types of immune cells whose role is better understood in boosting immune responses, such as natural killer cells and CD8+ T cells, both of which are responsible for attacking tumor cells. Focus on cells. . Although the importance of CD4+ cells in immune checkpoint inhibition therapy has only recently been discovered, the role of CD4+ cells in STING signaling has only been studied in the context of prophylactic vaccines rather than cell lines or therapeutic vaccines. .

Researchers have found that cancer vaccines alter the behavior of CD4+ T cells within tumors. The researchers tracked how tumors responded after treatment after depleting different immune cell populations. Depletion of macrophages and natural killer cells only partially compromised vaccine efficacy, but, as expected, CD8+ T cells were essential. However, CD4+ T cells were essential as well. In the absence of CD4+ T cells, vaccine-treated tumors behaved as if they had received no treatment at all.

CD4+ T cells can develop into several different subtypes with different functions. In tumors, CD4+ T cells often develop into the regulatory T (Treg) subtype that suppresses the immune response. However, in cancer vaccines, researchers found that STING signaling biases CD4+ T cells toward a T helper type I (TH1) phenotype, a helper T cell that activates other immune cells to attack tumor cells. has discovered.

“The key to exploiting CD4+ T cells in cancer therapy may lie in understanding how CD4+ T cells are polarized and activated,” He said. “The mechanistic insights gained from this study may inform future research on CD4+ T cells, allowing researchers to unlock the important therapeutic potential of these cells for human cancer patients. .”

The researchers believe that their approach could potentially be developed into a modular platform using different types of immune checkpoint blockade therapies. Future studies will explore therapeutic strategies to improve potential outcomes in patients with STING mutations, for example, by adjusting the dose and timing of treatment and exploring the use of other nanobodies that engage immune cells. will be fine-tuned.

This work was supported in part by the Koch Institute Frontier Research Program and Marble Center for Cancer Nanomedicine.