How One Type of Tumor Converts Innate Immune Cells to its Cause

Cancer is a corruption of growth. It is the processes of normal regeneration and tissue maintenance run wild, let loose from the usual state of careful regulation. One of the mechanisms by which many types of cancer prosper is via manipulation of the innate immune cells called macrophages, a type of myeloid cell, recruiting them to assist the cancer in many of the same ways that macrophages assist in regeneration and tissue maintenance. Solid cancer tissue contains large numbers of these tumor-associated macrophages.

Researchers are interested in finding ways to sabotage this relationship, particularly since macrophages are also capable of destroying errant cells, given the right prompts. Is it the case that tumor-associated macrophages could be reprogrammed into attacking every type of cancer that they have become a part of? Perhaps. Any approach to achieve that goal must be based on a better understanding of the interactions between cancerous cells and macrophages, however. That research is an ongoing project: today's scientific materials take a look at one of the less common cancers, and the mechanisms that this cancer employs to convert macrophages to the task of supporting its growth.

How Tumors Make Immune Cells 'Go Bad'

"Tumors recruit immune cells. These immune cells should be able to recognize and attack the tumor cells, but we found that the tumor cells secrete a protein that changes their biology, so instead of killing tumor cells they actually do the opposite." In comparing samples of a variety of soft-tissue sarcomas in humans and laboratory mice, researchers noted that most of these tumors have an abundance of immune cells called myeloid cells in their microenvironment. "It was striking that such a large percentage of the immune cells were myeloid cells, and we thought that since they obviously weren't killing the tumor cells, they must be doing something to promote tumor growth. And indeed, our analysis of tumor samples showed that many of the myeloid cells had adopted a tumor-promoting function."

To find out what was causing this change, investigators examined the proteins secreted by the tumor cells and the receptors on the surface of the myeloid cells - the elements cells use to communicate. "We examined the cross-talk between these two populations of cells. We found that the tumor cells expressed high levels of a protein called macrophage migration inhibitory factor (MIF), and that the myeloid cells had receptors to sense the MIF proteins. This makes them switch their biology and promote, rather than block, tumor growth." The investigators believe this information could be used to create novel therapies against soft-tissue sarcoma. A medication designed to stop cancer cells from expressing MIF could be tested in combination with existing therapies, for example, to see if it improves outcomes for patients.

Single-cell RNA-seq of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

The standard of care is unsuccessful to treat recurrent and aggressive soft-tissue sarcomas. Interventions aimed at targeting components of the tumor microenvironment have shown promise for many solid tumors yet have been only marginally tested for sarcoma, partly because knowledge of the sarcoma microenvironment composition is limited. We employ single-cell RNA sequencing to characterize the immune composition of a sarcoma mouse model, showing that macrophages in the sarcoma mass exhibit distinct activation states. Sarcoma cells use the pleiotropic cytokine macrophage migration inhibitory factor (MIF) to interact with macrophages expressing the CD74 receptor to switch macrophages' activation state and pro-tumorigenic potential. Blocking the expression of MIF in sarcoma cells favors the accumulation of macrophages with inflammatory and antigen-presenting profiles, hence reducing tumor growth. These data may pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care.

Comments

Investigating those mechanisms will not only help fighting cancer but might bring precious insights useful for regenerative medicine

Posted by: Cuberat at June 29th, 2022 10:27 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.