Under normal conditions, immune cells mature along a rigidly circumscribed path. Myeloid progenitor cells in the bone marrow can become monocytes (white blood cells that engulf pathogens), or they can differentiate down a parallel path to become granulocytes (white blood cells that create pus). Once they commit to one or the other path, they don't seem to be able to switch fates.

But work recently reported in Nature Immunology suggests that cancerous cells can re-engineer these immune cells, causing them to do just that. And they are induced to do so by the misregulation of one of the most well-studied oncogenes there is: the retinoblastoma (Rb) gene.

The immune system is normally capable of responding to cancer. But immature myeloid cells that tone down the immune response accumulate in the presence of tumors. These suppressor cells can be either monocyte-like or granulocyte-like, and it had been thought that they come from cells that are already committed to one of the two paths.

The researchers took both cell types out of mice with cancer and grew them in a culture mimicking the cancer context. They found that the monocyte-like cells grew much faster and survived much better than the granulocyte-like cells—yet somehow, the cultures were consistently enriched in the granulocyte-like suppressive cells. The researchers conclude that the pool of granulocyte-like cells “may be replenished from” the better-growing monocyte-like cells.

The same was true in mice: when the monocyte-like cells from mice with cancer were transferred into normal mice, they remained true to their fates. When they were transferred into new mice with cancer, they turned into granulocyte-like cells.

How does cancer manage to get these cells to switch fates? The researchers looked at the retinoblastoma protein (pRb), a known tumor suppressor (mutations that disable or diminish pRb yield uncontrolled cell growth, and thus cancer). The researchers found that in both mice and humans with cancer, the monocyte-like suppressor cells—the ones that switch fates—have low levels of pRb.

To demonstrate that pRb regulates this aberrant change of fate, the researchers showed that mice that lack pRb have excessive numbers of the granulocyte-like suppressor cells. When pRb is inserted into the monocyte-like cells in mice with tumors (which normally have low levels of the protein), the proportion of granulocyte-like cells is decreased.

What's not understood yet is how cancer cells cause the difference in pRb levels. Clearly, it's advantageous for them to do so, since it tones down the immune response. But there has to be some sort of signaling network that allows them to do so. Identifying it could ultimately allow it to be blocked, which may rev up the immune response to cancer.

Nature Immunology, 2013. DOI: 10.1038/ni.2526 (About DOIs).