New atlas details immune cell changes as disease progresses
Findings led to testing an antibody therapy in mice, with responses evident
Researchers in Belgium have developed an atlas to mark changes in distinct types of immune cells during multiple myeloma’s progression. Their work, in an established disease mouse model and patient tissue samples, is expected to aid research into the disease and ways of more effectively treating it.
Building on the changes seen, the team also conducted an initial evaluation of a potential myeloma therapy, which boosted certain immune cells and led to a significant anti-tumor response in the short term.
“We have developed a comprehensive and detailed immune atlas of the evolution in human and murine multiple myeloma disease progression,” Damya Laoui, PhD, a co-lead study author and head of the dendritic cell biology and cancer immunotherapy team at the VIB Center for Inflammation Research, in Flanders, said in a center press release.
“This new tool is freely accessible and can significantly contribute to immune-based patient stratification and facilitate the development of novel and durable immunotherapeutic strategies in multiple myeloma,” Laoui said.
Atlas into the tumor-immune microenvironment at various myeloma stages
The study, “A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages” was published in the Journal of Hematology & Oncology.
Myeloma is a blood cancer that affects plasma cells, a type of white blood cell that’s normally responsible for producing antibodies. Cancerous plasma cells grow out of control in the bone marrow, disrupting the production of other blood cells. Because myeloma cells form in more than one location within the bone marrow, it’s called multiple myeloma.
Despite high initial response rates to current therapies, most myeloma patients eventually relapse, and the disease becomes resistant to multiple lines of treatments: a status called relapsed/refractory disease. New types of immunotherapy, including those based on immune T-cells modified to attack myeloma cells, could be promising options for hard-to-treat disease.
“Immunotherapies designed to stimulate the patient’s immune response show significant clinical potential,” the researchers wrote, noting some are in clinical testing in other cancers.
However, the efficacy of such immunotherapies often depends on the tumor-immune microenvironment (TME) — the area surrounding cancer cells, which includes blood vessels, immune cells, and various other cells and signaling molecules that help drive cancer growth and spread. Cancer cell growth often is promoted by an immunosuppressive TME, in which the immune system is prevented from attacking the cancer.
As such, “it remains critical to gain insights into the dynamic changes within the immune cell compartment throughout disease progression,” the researchers wrote.
Immune cell changes in bone marrow, spleen seen in mice and patient cells
Working in an established multiple myeloma mouse model, the scientists developed an atlas of the tumor-immune microenvironment at different stages of myeloma by analyzing the gene activity in individual immune cells over time. The findings then were correlated with samples from relapse/refractory multiple myeloma patients.
Researchers detected at least 17 types of immune cells and their precursors in the bone marrow and spleen of the mice. In the bone marrow, some immune cells — including conventional dendritic cells, T-cells, and natural killer T-cells — increased with tumor progression, while others, such as B-cells, decreased. Similar but less pronounced trends were seen in the spleen, expect for immune neutrophils, which upon myeloma progression decreased in the bone marrow but increased in the spleen.
Like the mouse data, increases in certain immune cells, including conventional dendritic cells, cytotoxic T-cells, natural killer cells, and natural killer T-cells, were seen in samples from patients with disease progression.
“After correlating immune changes observed in our [mouse] dataset with those in human patients across various disease stages, we were able to validate the dynamic changes upon disease progression, demonstrating how accurately this mouse model represents the human condition,” said Emma Verheye, the study’s first author and a PhD candidate at VIB.
In more detail, the T-cells that increased with disease progression showed exhaustion, meaning they lost their ability to kill cancer cells because of prolonged activation. In the disease’s early stages, neutrophils appeared normal, but with progression acquired a behavior that promoted tumor growth. Moreover, the activation state of conventional dendritic cells declined in later stages of the disease.
Antibody therapy targeting CD40 protein on dendritic cells shows promise
Building on these results, the team then tested the therapeutic potential of an antibody targeting a protein on conventional dendritic cells called CD40, which boosts their activation and is thought to promote an anti-tumor immune response.
Using tissue samples from myeloma mice and patients, the anti-CD40 therapy successfully activated the conventional dendritic cells, followed by T-cells. It also decreased blood levels of M-protein, a marker for myeloma, and reduced the tumor load. Similar results were observed following a single dose of the therapy in the living myeloma mouse model.
“Our novel tool revealed cDCs [conventional dendritic cells] as a targetable population in [multiple myeloma],” said Kim De Veirman, PhD, a study co-lead at the Vrije Universiteit Brussel. “We therefore performed the first pre-clinical evaluation of the DC-activating [anti]-CD40 therapy on murine and human samples, and in the [multiple myeloma] mouse model.”
Treatment with the “[anti]-CD40 led to a successful cDC- and subsequent T-cell activation, and a significant short-term anti-tumor response,” De Veirman added. “These positive results show that we have developed a valuable research tool for the [multiple myeloma] research community.”
The scientists called for further study into an [anti]-CD40 therapy for multiple myeloma, noting that ongoing clinical trials are investigating such treatments in people with solid tumors and B-cell lymphoma.
“The fact that [multiple myeloma] patients are not included in these trials, highlights the need for pre-clinical evidence of the efficacy of [anti]-CD40 therapy,” they wrote, noting their study “provides the first pre-clinical evidence of the immune activating and therapeutic potential” of such a treatment in the disease.
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