Study shows how tumours turn immune cells into enablers of their growth

26 Oct 2021
Study shows how tumours turn immune cells into enablers of their growth

A Ludwig Cancer Research study has identified a means by which cancer cells engineer the conversion of immune cells known as macrophages from destroyers of tumours to supporters of their growth and survival.

The new research, led by Ludwig Lausanne’s Ping-Chih Ho and postdoctoral fellow Giusy Di Conza, reveals that in mouse models of the skin cancer melanoma, this transformation of macrophages within tumours is prompted by a fat molecule, or lipid, released by cancer cells.

The study, published in the current issue of Nature Immunology, also identified some of the key events and molecular players that drive this “polarisation” of tumour-associated macrophages (TAMs). Ho, Di Conza and colleagues show that the lipid responsible, β-glucosylceramide, binds to a receptor on TAMs, triggering a stress response within a tubular cellular organelle known as the endoplasmic reticulum (ER).

This, in turn, sets off at least two signalling cascades within the cell, which drive the expression of genes in macrophages that facilitate their transformation.

“Aside from exposing a previously unknown mechanism by which tumours manipulate the immune system to their own benefit, our study identifies signalling events that could be pharmaceutically targeted to push macrophages back towards an anti-tumour phenotype for cancer therapy,” said Di Conza, who is the first author of the paper.

Ho, Di Conza and colleagues began these studies with the observation that pro-tumour TAMs display two curious traits: a higher than usual lipid content and swelling of their ER. Swelling is usually a sign of ER stress, and the team also detected elevated levels of stress-response proteins in the pro-tumour TAMs. One such protein—a form of XBP1 recently linked to suppressing the function of other immune cells—appeared to be necessary for skewing TAMs towards a pro-tumour state, or phenotype.

These observations fit with other emerging evidence that abnormal lipid metabolism in cancer cells causes the accumulation of lipids in the tumour microenvironment that inhibit anti-tumour immunity.

“We know that metabolites in the tumour are important for shaping not only the phenotype of the tumour, but also the immune cells residing in the tumour microenvironment,” said Di Conza. “So, we wondered whether there is a metabolic link between cancer cells and macrophages that tells a macrophage to become a bad guy.”

The team tested this possibility by removing lipids from the conditioned medium in which the mouse tumour cells were cultured. Doing this prevented TAM conversion into the pro-tumour phenotype.

Next, the team sought to identify the particular lipid triggering TAM polarisation. Ironically, they were assisted in this difficult task by the COVID-19 pandemic. Unable to enter the lab during the pandemic lockdown, Di Conza passed some of the time reviewing data on genes involved in lipid recognition and binding. There, she found a new lead.

A lipid receptor found on the surface of macrophages, known as Mincle, was conspicuously active when exposed to the medium in which mouse cancer cells were growing. Mincle can induce ER stress responses and the accumulation of lipids in macrophages—the very traits that Di Conza and her team had observed in pro-tumour TAMs.

When the researchers blocked Mincle activity using an antibody, they observed a marked reduction in TAM polarisation towards a pro-tumour state. 

Mincle’s involvement led the researchers to take a closer look at β-glucosylceramide, a lipid released into the tumour microenvironment that binds to Mincle. Disabling its production by cancer cells resulted in fewer pro-tumour TAMs and slowed tumour growth in mice.

“Based upon the finding, our speculation is that cancer cells upregulate this lipid as a response to stress,” said Ho, associate member of the Ludwig Institute for Cancer Research, Lausanne. “The secretion of β-glucosylceramide then informs surrounding cells that those cancer cells need help. It also helps facilitate the functional skewing of macrophages in the tumour microenvironment to become pro-tumourigenic.”

Subsequent experiments further revealed that XBP1 is activated in pro-tumour TAMs, and removing this gene slowed tumour growth, indicating that XBP1 is not only vital for TAM polarisation but also supports cancer cell survival. 

Further, XPB1 alone is not sufficient to promote the pro-tumour phenotype. Other experiments indicated that another signalling cascade was coordinating with the one involving XBP1 to induce TAM polarisation. This turned out to be a pathway involving a signalling protein and transcription factor named STAT3, which binds DNA and directly regulates the expression of genes.

Now that some of the key events and molecular players in TAM polarisation have been identified, it may be possible to target them pharmaceutically to slow or even reverse the process.

Source: Ludwig Institute for Cancer Research