Tag Archives: T-cells

Breast cancer cell.

Cell maps reveal how the body fights off cancer

Two new papers published in the journal Cell offer the first high-detail maps of the immune system cells which surround tumors.

Breast cancer cell.

Breast cancer cell seen under a scanning electron microscope.
Image credits National Cancer Institute.

The data could help guide research into new targets for cancer therapies and pinpoint biological markers which can be used to determine the likelihood of patients to respond to particular therapies or when best to start administering them.

What type of cells surround a tumor and the way they respond to it (especially immune system cells which bunch up at its border and fight towards the core) usually makes or breaks immunotherapy aimed at fighting the disease. Recent advances in the ability to characterize those individual cells are now driving a push to catalog and learn more about how the cells impact the progression of tumors.

Act faster, use more data

The first of the papers was published by a team led by Bernd Bodenmiller, a systems biologist at the University of Zurich, Switzerland. The team mapped the body’s immune response for clear cell renal cell carcinoma, a form of kidney cancer. The researchers focused on two types of immune cells — T cells and macrophages. Both of them are involved in either increasing or suppressing the body’s immune response to a tumor by altering the proteins they express.

Bodenmiller’s team worked with samples from 73 patients with kidney cancer and 5 samples from healthy individuals as a control group. They analyzed 3.5 million cells looking at the expression of 29 proteins used to characterize macrophages, and 23 to characterize T cells.

They found that the T cell populations and those of the macrophages were more varied than previously believed. They also note that patients with a particular combination of T cells and macrophages tended to have fast-progressive cancers. All in all, their results shows that the current practice of looking only at one or two major proteins to determine the state of a T cell or macrophage falls very short of giving oncologists the full picture.

The second study was led by oncologist Miriam Merad of the Icahn School of Medicine at Mount Sinai, New York City. His team compiled an atlas of immune cells associated with early-stage lung cancer. By comparing healthy lung tissue and blood with tumor tissue, they found that immune cells in the vicinity of tumors start to alter themselves since the early stages of the disease. This suggests that cancer treatments which target the immune system can be employed from the start, without having to wait for more advanced stages of the disease.

Understanding how our immune systems change in response to cancer would let doctors tailor our interventions against the disease to work in tandem with our bodies — so work like that performed by these two teams is hugely important for patients. The studies themselves are too small to change how we go about treating cancer right now — but they offer a wealth of possibilities. As more researchers double-check the findings and add new data on the foundation these two papers set in the coming years, we’re likely to see cancer treatments becoming more and more personalized.

The first paper “An Immune Atlas of Clear Cell Renal Cell Carcinoma” has been published in the journal Cell. The second paper “Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses” has been published in the journal Cell as well.

Chinese scientists prepare for first human CRISPR gene-editing trial

Image credit Pixabay

Image credit Pixabay

The CRISPR gene-editing technique has opened up a lot of doors in the scientific world – it has been used to cut out HIV genes from live animals and genetically modify human embryos. Although its benefits are indisputable, experiments such as the latter have caused controversy, as some believe that they bring us closer to changing what it means to be human.

Now, Chinese researchers from the Sichuan University’s West China Hospital have announced their plans to run a clinical trial where CRISPR will be used to modify human beings for the first time ever. In particular, the team plans to work on patients with lung cancer and turn off genes that encode a specific protein linked to a lower immune response.

Although China has come under scrutiny for their promotion of using gene-editing techniques on human beings, the new effort isn’t as controversial as the aforementioned study on human embryos. In fact, a federal panel gave the green light for a similar U.S. study back in June.

“Our goal is to develop a new type of immunotherapy using gene-editing technology that will enable the engineered immune cells to be more potent, survive longer, and thereby kill cancer cells more effectively,” the U.S. team said of their research.

The Chinese clinical trial is set to start next month and will gather T cells, which play a central role in human immunity, from patients with incurable lung cancer and conduct genetic modifications in these cells. These modifications will disable a gene that encodes the PD-1 protein, which has been shown to inhibit the immune response that protects healthy cells from attack.

After the T cells have been successfully modified and examined for editing errors, they will be allowed to multiply and then injected back into the patient’s bloodstream. Ideally, the edited cells will bolster the immune response of the lung cancer patient and aid it in attacking and killing tumor cells.

Thirty candidates are set to participate in the trial, although just one will be injected with a three dose regimen of edited cells, after which the team will monitor the patient for any positive and negative responses to the treatment before proceeding with further trials.

The normal mouse thymus (left) contains only a small fraction of B-cells (red). If the gene FOXN4 is activated, a fish-like thymus with many B-cells develops. Image: Max Planck

Resetting the immune system back 500 million years

Researchers at the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE)  re-activated the expression of an ancient gene in mice. To their surprise, the gene in question which is dormant in all mammalian species caused the mice to develop  fish-like thymus. The thymus is an organ of paramount importance to the adaptive immune system, but in this particular instance, the thymus produced not only T cells, but also served as a maturation site for B cells – a property normally seen only in the thymus of fish. So, what we’re seeing is a resetting of the immune system to a state similar to what it was like 500 million years ago, when the very first vertebrates began to emerge. By closely following how these gene works, the scientists hope to build a model that will explain how the thymus evolved during the past hundreds of millions of years.

An ancient immune system, today

T-cells are a type of white blood cell that circulate around our bodies, scanning for cellular abnormalities and infections, and are essential to human immunity. These are matured by the epithelial cells in the thymus, but genetically-wise it’s the FOX1 gene that triggers their development. FOX1’s evolutionary ancestor is FOX4, an ancient gene that lies dormant in most vertebrates except jawed fish, such as cat sharks and zebra fish.

The team led by Thomas Boehm, director at the MPI-IE and head of the department for developmental immunology, activated FOX4 in mice. When both FOX1 and FOX4 are simultaneously activated, the researchers found the mouse thymus exhibited properties similar to those found in a fish. Coupled with previous findings, the results suggest that that thymus as we know it today in most vertebrates evolved from and was prompted by the FOX4 gene.  Through  an evolutionary gene duplication FOX1 was born. Initially  both genes must have been active, until finally only FOXN1 was active in the thymus.

The normal mouse thymus (left) contains only a small fraction of B-cells (red). If the gene FOXN4 is activated, a fish-like thymus with many B-cells develops. Image: Max Planck

The normal mouse thymus (left) contains only a small fraction of B-cells (red). If the gene FOXN4 is activated, a fish-like thymus with many B-cells develops. Image: Max Planck

A surprising find was that not only T-cells developed in the thymus of the mice, but also B-cells. Mature B-cells are responsible for antibody production. In mammals, they normally do not mature in the thymus, but in other organs, such as the bone marrow.

Boehm says that it’s not yet clear whether the B-cell development is based on the migration of dedicated B-cell precursors to the thymus, or to maturation from a shared T/B progenitor in the thymus itself.  Nevertheless, it’s remarkable how the researchers have uncovered a particular evolutionary innovation that occurred in an extinct species. Retracting evolutionary steps in our collective ancestral background might provide insights we dare not dream of.