The Immune System’s Fight Against Cancer

The human immune system has developed a remarkable capability to combat cancer cells. One of its key defenders is a specific type of white blood cell known as a macrophage.

The term comes from Greek, meaning “big eater,” which is quite fitting given that these cells have a voracious appetite for cancerous cells. Interestingly, macrophages can also signal an “eat me” alert from within tumors, prompting other immune cells, like T cells, to jump into action.

While these cells are a promising focus for cancer research, many advanced therapies haven’t fully tapped into their potential yet. However, a research group from the University of Southern California (USC) might have discovered a breakthrough.

Their recent work involves genetically engineering cells that develop into macrophages in a lab setting—specifically, macrophage progenitor cells. These aren’t exactly stem cells; rather, they are the precursors that eventually mature into stem cells, yet they possess a unique feature:

They have the ability to replicate themselves indefinitely.

Biologist Qi-Long Ying at USC elaborates, stating that the general consensus has been that self-renewal in the blood system mainly belongs to stem cells that can create any kind of blood or immune cell. This study suggests that, under appropriate conditions, these progenitor cells can also self-renew, continuously dividing while maintaining their identity and capacity to produce functional immune cells.

This advancement could serve as a scalable foundation for developing cell therapies aimed at cancer, infectious diseases, and potentially numerous other conditions.

A well-known cancer therapy, CAR-T, involves extracting a patient’s T cells, genetically modifying them to enhance their cancer-fighting abilities, and then returning them to the patient’s body. Various versions of CAR-T have shown significant success in clinical trials, greatly increasing patients’ lifespans.

However, while beneficial for blood cancers, CAR-T therapies haven’t proved as effective against solid tumors.

Macrophages are typically the most prevalent immune cells found within tumors, but they are challenging to manipulate in laboratory environments. They often struggle to proliferate outside of the human body and can be difficult to store and freeze over long periods.

Nevertheless, prospects for therapies resembling CAR-M, which would utilize macrophages instead of T cells, are still alive.

The progenitor cells for macrophages, called granulocyte-monocyte progenitors (GMPs), could be the solution. By working with both mouse and human GMPs, Ying’s team has identified the specific nutrients these cells need to thrive, providing a specialized mix of substances at precise stages of their development.

The intention is that this continuous supply of GMPs might support future cancer immunotherapies.

In experimental settings, the engineered GMPs produced effective CAR-Ms. When researchers injected these cultivated GMPs into mice with blood cancers and solid tumors, they discovered that the progenitor cells successfully generated a consistent supply of macrophages and other immune components.

Unlike direct injections of macrophages, which tend to stay localized, these GMPs disseminated throughout the mice’s bodies and halted cancer growth in both blood and solid tumors.

Ravi Majeti, a collaborator from Stanford University, points out that this technique for amplifying and engineering GMPs opens up numerous possibilities for real-world applications, much like those achieved with T cell expansion and engineering. There’s still a lot to discover.

Interestingly, while scientists have long tried to establish which T cells should be targeted for CAR-T therapies, this new research indicates that focusing on the progenitors of immune cells may offer a wider range of success.

Ying concludes that the future of immunotherapy could hinge not just on the design of better CAR receptors but also on selecting the appropriate developmental stage of the cell.

The study has appeared in the scientific journal Cell.