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Metastatic breast cancer has no cure and has proven stubbornly resistant to one of the most innovative and promising new cancer treatments: immunotherapy.

Now, researchers at Washington University School of Medicine in St. Louis have identified a way to treat the area surrounding breast tumors that have spread to bone so that such tumors become vulnerable to attack by the body’s immune system. When the researchers boosted the activity of certain immune cells, called T cells and macrophages, these immune cells worked together to clear metastatic breast tumors that had spread to the bones of mice, and continued to eliminate tumor cells that eventually returned.

The study is published March 8 in Cancer Discovery, a journal of the American Association for Cancer Research.

Macrophages are myeloid immune cells that attack cancer cells through the body’s innate immune response to general threats, such as tumors or viruses. Such macrophages further activate T cells by showing the T cells what they should be looking for, thereby harnessing the adaptive immune response as well. In this case, these macrophages present T cells with bits of recognizable tumor — called tumor antigens — from dead cancer cells, and the antigens direct the killing activities of T cells.

“After breast cancer has spread to other parts of the body, it becomes extraordinarily difficult to treat; current therapies can only try to slow it down,” said senior author Sheila A. Stewart, PhD, the Gerty Cori Professor of Cell Biology & Physiology. “About 70% of patients with metastatic breast cancer have tumors that have spread to their bones. Our study suggests we may be able to use two treatments — one to sensitize the myeloid tumor microenvironment to immunotherapy, and one to activate T cells — to target these bone metastases in a way that eliminates the tumor, prevents the cancer from returning and protects against bone loss in the process.”

Stewart, also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, and her colleagues found that blocking a molecule called p38MAPK reprograms the tumor microenvironment to become more vulnerable to attack by the immune system, including by immune cells and signaling molecules called anti-tumor cytokines. While a p38MAPK inhibitor alone reduced tumor size, it didn’t eliminate the tumor entirely. So, the researchers investigated whether adding another therapy that activates T cells and boosts their ability to find and destroy the tumor cells could be more effective at eliminating the metastatic cancer cells.

Common immunotherapies — called immune checkpoint inhibitors — are often described as “taking the brakes off” immune T cells, ushering them into battle against cancer. In this case, Stewart described the new approach as “hitting the gas” on T cells, supercharging them to be more effective against the cancer.

The researchers investigated two models of human metastatic breast cancer in mice and found that the metastatic tumors were eliminated in mice that received a p38MAPK inhibitor and an immune therapy called an OX40 agonist, which binds and activates T cells. All these mice were still alive and tumor-free at least 80 days after treatment. Among mice receiving either of the two treatments alone, only about half of them were still alive 60 days after treatment.

“If we targeted the microenvironment to make it more sensitive to T cells and simultaneously hit the gas on the T cells, all of the mice were cleared of the metastatic tumors,” Stewart said. “If we came back after two weeks and challenged the mice again with the same tumor cells, their immune systems could clear those cells as well. It appears that their immune systems developed long-term memory and knew to attack those returning cancer cells. The mice look like they’re basically vaccinated against the cancer.”

Three different OX40 agonists are being investigated in phase 2 clinical trials for cancer, including breast cancer. And p38MAPK inhibitors have been investigated in a number of inflammatory disorders, including rheumatoid arthritis and chronic obstructive pulmonary disease.

“We are hopeful that our study will interest companies that make these drugs, so that we can work toward developing a clinical trial that could investigate this strategy in patients with metastatic breast cancer,” Stewart said.

Jumping genes are short sections of DNA that have been incorporated randomly into the human genome over the long course of evolution. Also called transposable elements, these pieces of DNA have been implicated in the development of cancer.

But new research from Washington University School of Medicine in St. Louis suggests that transposable elements in various cancers potentially may be used to direct novel immunotherapies to tumors that don’t typically respond to immune-based treatments.

The study is available online in the journal Nature Genetics.

Immunotherapy is often most effective in tumors with numerous mutations, such as skin and lung cancers. Mutations in DNA cause cancer cells to produce unusual proteins that distinguish tumor cells from normal cells and serve as targets — called tumor antigens — for immunotherapies, such as antibodies, vaccines and genetically engineered CAR-T cell therapies. But many tumor types don’t contain large numbers of mutations and are therefore harder for the immune system to identify as a threat.

“Immunotherapy is an extremely promising approach for cancer treatment, but current therapies don’t work in many tumor types in which the mutation burden is low,” said senior author Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine. “We are excited about this research, because it opens up an entirely new way to identify tumor antigens in types of cancer that have previously been invisible to immunotherapy.”

Jumping genes — believed to have possibly originated from viruses — usually are found in parts of the genome that are inactive in adult tissues. But past work by Wang and his colleagues showed that these transposable elements sometimes can function as hidden on switches, forcing a gene to be turned on all the time, even though it should not be. As these stealthy on switches drive cancer growth, they also can churn out unusual pieces of proteins that are unique to the tumor and not present in normal cells.

In an analysis of 33 tumor types from the National Cancer Institute’s The Cancer Genome Atlas Program, the researchers identified 1,068 transposable element-derived transcripts — or sections of RNA made by the cancer cells — with the potential to produce tumor antigens that could serve as targets for new immunotherapies.

Wang and his colleagues determined that these possible tumor antigens were present on the surfaces of cancer cells, making them ideal for targeting with immunotherapies. Importantly, they found that almost 98% of the more than 10,000 tumors analyzed had at least one potential antigen target arising from a transposable element. Most tumors had from two to 75 possible antigens.

In another important finding, the researchers showed that many of the candidate proteins that could serve as antigens were present in multiple tumors and, in some cases, across tumor types. Wang and his colleagues speculated that this raises the possibility of a universal antigen-based therapy that could treat multiple tumors with a single cocktail targeting several of the most common tumor antigens that arise from jumping genes. For example, the data suggest that a vaccine with a combination of 20 of the most common protein targets could cover about 75% of patients across 27 cancer types.

“With this analysis, we can envision the design of a cancer vaccine that targets the top five or top 10 most common tumor proteins that are caused by transposable elements,” said Wang, also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “This type of vaccine is still just an idea, but we are excited about the potential, because these common targets could cover a large fraction of tumors. Much more work is necessary, but we are hopeful that this analysis can serve as a starting point for the development of effective immunotherapies across many more cancer types.”

Immunotherapy has transformed cancer care. In advanced melanoma, for example, the most fatal form of skin cancer, the five-year survival rate has risen from less than 10% to more than 50% since immunotherapy was introduced in 2011. Still, only about half of melanoma patients respond to immunotherapy, and those who do not respond face a difficult future.

Researchers at Washington University School of Medicine in St. Louis have discovered that the difference between people who do and do not respond to immunotherapy may have to do with an immune cell known as CD5+ dendritic cells because they bear the protein CD5 on their outer surfaces. Their research showed that people with a variety of kinds of cancers, including melanoma, lived longer if they had more CD5+ dendritic cells in their tumors, and that mice that lacked CD5 on their dendritic cells were unable to respond well to immunotherapy.

The findings, published Feb. 17 in the journal Science, suggest that a supplementary therapy designed to increase the number or activity of CD5+ dendritic cells potentially could extend the lifesaving benefits of immunotherapy to more cancer patients.

“Immunotherapy has revolutionized the field of cancer therapy, but there are a lot of patients with cancer who don’t benefit from it,” said senior author Eynav Klechevsky, PhD, an assistant professor of pathology & immunology and a researcher at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Part of the reason some people do not respond well to some forms of immunotherapy is because this population of dendritic cells is reduced dramatically. We’re developing some novel immune-based approaches to boost the activation of these CD5-expressing dendritic cells with a goal of helping more patients respond to immunotherapy.”

The immune system defends the body against cancer by activating immune cells known as T cells to recognize and kill tumor cells. In response, tumor cells manipulate the immune checkpoint system — a safeguard that prevents T cells from mistakenly attacking healthy cells — to hoodwink T cells into leaving them alone. Immune checkpoint blockade therapy works by thwarting tumor cells’ manipulations, thereby freeing T cells to recognize and destroy tumors. But even with therapy, some people’s T cells are unable to do their job effectively.

Klechevsky and colleagues — including first author Mingyu He, PhD, a staff scientist, and co-author Kate Roussak, MD, a postdoctoral researcher — suspected that people who don’t respond to immunotherapy may have a problem with their dendritic cells. If T cells are the players on a soccer field, dendritic cells are the coaches who get the players pumped up for the game and give them instructions. Without dendritic cells, T cells are subdued and aimless.

By analyzing data in The Cancer Genome Atlas — a public database with information on 20,000 tumors representing 33 cancer types — Klechevsky and colleagues discovered that patients with types of skin, lung, bone and soft tissue, breast and cervical cancers fared better if they had higher levels of CD5+ dendritic cells in their tumors.

Further experiments with human cells and mice showed that CD5+ dendritic cells are required for effective T cell activity against tumors. CD5+ dendritic cells from people powerfully induced T cells to activate and multiply. Mice with tumors responded only weakly to immunotherapy and failed to reject the tumors if they lacked CD5 on their dendritic cells.

The findings suggest that the amount of CD5+ dendritic cells inside tumors could be used to help doctors assess which patients are most likely to benefit from immunotherapy. They also suggest that increasing the numbers or the activity of such dendritic cells potentially could help more people benefit from immunotherapy. As part of this study, the researchers discovered that the immune protein IL-6 increases the amounts of CD5+ dendritic cells.

“We still don’t completely understand how immunotherapies work,” Klechevsky said. “This study indicates that there is more we can do to increase the efficacy of these treatments. I’m confident that if we can find ways to harness these cells or expand these cells in patients, we can help more people.”