Cancer in Children: Immune Response Vulnerability

Scientists led by Sabine Taschner-Mandl, Ph.D., St. Anna Children’s Cancer Research Institute, and Nikolaus Fortelny, Ph.D., Paris Lodron University of Salzburg, are the first to use contemporary single-cell sequencing technology to examine bone marrow metastases from juvenile nervous system malignancies. Cancer cells, it turns out, inhibit cells in their environment from battling the tumor—a process that can be reversed with medication. Nature Communications published the findings.

The most common solid tumor in newborns and young children is neuroblastoma. Despite progressively improved treatment choices, more than half of individuals with a particularly aggressive variety (high-risk neuroblastoma) experience relapses. “We specifically studied bone marrow metastases because recurrences often originate there. The tumor cells seem to manipulate their environment so that it supports their growth instead of fighting them,” explains Sabine Taschner-Mandl, Head of the Tumor Biology Group at St. Anna Children’s Cancer Research Institute (St. Anna CCRI).

How cancer cells influence their surroundings

Using single-cell transcriptomics and epigenomics, the researchers investigated the cell architecture and cell-cell communication of neuroblastoma metastases from two major genetic subgroups (MYCN amplification or ATRX mutations) and those without such modifications. “Until now, only primary tumors have been studied in such detail, but not neuroblastoma metastases,” says Irfete Fetahu, Ph.D., co-first author as well as co-corresponding author of the study and postdoc in the Tumor Biology Group.

The team examined the interaction of metastatic tumor cells with healthy bone marrow cells in more detail. “We developed algorithms that enabled us to analyze different cells in the bone marrow as well as to model their interactions,” said Fortelny, head of the Computational Systems Biology Group, Paris Lodron University of Salzburg.

“Our analysis has shown that certain cells, so-called monocytes, react to unwanted invaders. In the course of this, they foster growth processes and release cytokines that stimulate tumor growth,” explains Fetahu. Interestingly, investigations at the epigenetic level showed that although monocytes in the tumor microenvironment are activated to attack cancer cells, they are unable to respond appropriately to these signals. “These monocytes receive contradictory messages. As a result, they are no longer able to fight the tumor,” Fetahu said.

The communication between neuroblastoma cells and bone marrow or monocytes is to a large extent regulated by the proteins MK (midkine), MIF (macrophage migration inhibitory factor) and associated molecules. Signaling pathways controlled by these proteins are upregulated in immune cells. “Drugs targeting MK and MIF disrupt this pathological interaction and are currently under investigation. Through selective inhibition, it could be possible to return these pathologically altered monocytes to their original state,” says Taschner-Mandl.

Metastases behave in different ways

The researchers also discovered that cellular plasticity, or the ability of cells to alter in response to environmental cues, is preserved throughout metastasis. Furthermore, the gene expression of metastatic tumor cells is affected by the neuroblastoma genetic subtype. When neuroblastoma cells with MYCN amplification spread from the main tumor to the bone marrow, they change relatively minimally, whereas tumor cells with ATRX mutation exhibit substantial changes.

“The genetics of the tumor lead to characteristic signals and thus very specific changes in the microenvironment of the bone marrow, which is expressed in individual signatures,” says Taschner-Mandl. “This could explain why neuroblastoma patients with ATRX mutations often respond poorly to therapy.”

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