Putting STING into Cancer Immunotherapy | MIT News

Immune checkpoint blocking therapies have been revolutionary in the treatment of certain types of cancer, becoming one of the most promising treatments for diseases such as melanoma, colon cancer and non-small cell lung cancer. cells.

While in some cases checkpoint blockade therapies elicit a strong immune response that eliminates tumors, checkpoint inhibitors do not work for all types of tumors or all patients. In addition, some patients who initially benefit from these therapies see their cancers recur. Only a small minority of patients treated with checkpoint blocking therapies see lasting benefits. Researchers have developed various combination therapy strategies to overcome resistance to checkpoint blocking therapies, with the STING pathway emerging as one of the most attractive avenues of research.

In a study published in Advanced Healthcare Materials, a team of MIT researchers has developed a therapeutic cancer vaccine capable of restoring STING signaling and eliminating the majority of tumors in mouse models of colon cancer and melanoma, with minimal side effects. The vaccine also inhibited metastasis in a mouse model of breast cancer and prevented tumor recurrence in cured mice.

“We have repurposed a naturally existing adapter protein into a novel dual-function cancer vaccine that initiates and maintains effective anti-tumor immunity. The protein complex stimulated a robust immune attack and helped form long-term memory against tumors in mouse models of colon cancer and melanoma,” says Angela Belcher, lead author of the study, member of the Koch Institute for Integrative Cancer Research, and the head of the Department of Biological Engineering at MIT.

The study was led by MIT postdoctoral fellow Yanpu He and conducted in collaboration with the lab of Paula Hammond, who is also a fellow at the Koch Institute, a professor at the Institute at MIT, and head of the Department of Chemical Engineering. from MIT. Other authors of the article include Celestine Hong, Shengnan Huang, Justin Kaskow, Gil Covarrubias, Ivan Pires and James Sacane.

Components of a vaccine

Immune checkpoints are a key part of a system that helps the immune system differentiate between the body’s own healthy cells and threats such as harmful bacteria or cancer cells. When checkpoint proteins on the surface of immune cells bind to partner proteins on other cells, the interaction results in a signal that prevents T cells and other immune cells from mounting an attack. By presenting the same type of partner proteins, cancer cells can escape destruction by the immune system. Immune checkpoint blocking therapies – the discovery of which was recognized with the 2018 Nobel Prize in Physiology or Medicine – work by binding to cancer cell partner proteins and allowing the immune system to respond.

The STING pathway holds promise as a partner in immune checkpoint blocking therapies due to its key role in increasing the immune response to pathogens and cancer cells. The pathway is also known to impact the immune system in other ways, including the maturation, specialization, and activation of certain types of immune cells.

Although there are many ongoing clinical trials that combine immune checkpoint blockade with STING-targeted therapy, few have received approval from the U.S. Food and Drug Administration, largely because they can cause severe toxic and inflammatory side effects when administered systemically. Side effects can be limited by injecting STING directly into the tumor, but this strategy still leaves a serious challenge unaddressed: 19% of people carry mutated versions of the STING gene and do not respond to STING-targeted therapies.

In previous work, researchers attempted to address this challenge by designing a protein complex capable of restoring STING signaling in cell lines lacking STING protein or displaying a mutated and ineffective version of the gene. The complex combined a piece of the STING protein responsible for triggering downstream signaling with cGAMP, a small molecule that stimulates the STING pathway.

In the current study, the team added an additional component to the STING-cGAMP complex: a smaller form of an antibody known as a nanobody carrying immune checkpoint blockade therapy.

After direct injection into tumors, the cancer vaccine eliminated 70-100% of tumors in mouse models of colon cancer and melanoma. The researchers found that most of the vaccine remained in the tumor and the treated mice lost minimal weight, suggesting that the risk of systemic side effects is low. The cured mice remained tumor-free after six months of observation, and when the researchers restimulated the mice with tumor cells to simulate cancer recurrence, 100% of those mice rejected them through immune memory. When mice with knocked out STING genes were treated, the vaccine still restored STING signaling and significantly reduced tumor size, but not as effectively as in mice with normal STING function.

“With further development, this platform not only promises to increase the effectiveness of checkpoint blockade therapies and prevent recurrence more broadly for cancer patients,” Belcher says, “but it could lead to a new cancer treatment that could make checkpoint blockade therapy viable for large fractions of the human population with loss-of-function STING mutations.

A surprising role for CD4+ T cells

When the researchers studied the mechanisms of the tumor response to the vaccine, they discovered – contrary to their expectations – that a subtype of T cells called CD4 + T cells played a central role in obtaining anti-tumor immunity. .

In clinical cancer treatments, CD4+ T cells play various roles in the immune system and are commonly associated with immunosuppression. Subsequently, most research on checkpoint blockade therapies and the STING pathway has focused on other types of immune cells whose role in increasing immune responses is better understood – for example, natural killer cells and CD8+ T cells, both of which are responsible for attacking tumor cells. . The importance of CD4+ cells has only recently been discovered for immune checkpoint blocking therapies, whereas their role in STING signaling has only been studied in cell lines or as part of preventive vaccines and non-therapeutic.

The researchers found that the cancer vaccine altered the behavior of CD4+ T cells in tumors. After exhausting different populations of immune cells, the researchers followed the tumors’ response after treatment. Although the depletion of macrophages and natural killer cells only partially compromises the efficacy of the vaccine, CD8+ T cells were, as expected, essential. However, CD4+ T cells were also essential. Without CD4+ T cells, tumors treated with the vaccine behaved as if they had received no treatment.

CD4+ T cells can develop into several different subtypes with different functions. In tumors, CD4+ T cells frequently develop into a regulatory T (Treg) subtype that suppresses the immune response. But with the cancer vaccine, researchers found that STING signaling polarized CD4+ T cells into the type I (TH1) helper T phenotype, a helper T cell that activates other immune cells to attack tumor cells. .

“A key to leveraging CD4+ T cells in cancer therapies may be understanding how they are polarized and activated,” He says. “The mechanistic insights from this study could inform future work on CD4+ T cells, allowing researchers to unlock the important therapeutic potential of these cells for human cancer patients.

The researchers believe their approach could be developed into a modular platform, using different types of immune checkpoint blocking therapies. In future work, they plan to refine their therapeutic strategy to improve potential outcomes for patients with STING mutations, such as adjusting the dosage and timing of treatment and exploring the use of other nanobodies to engage the immune cells.

The study was funded in part by the Koch Institute Frontier Research Program and the Marble Center for Cancer Nanomedicine.