When it comes to the immune system, attention seems to focus on its protection. But equally important is how the unleashed immune response becomes a threat. In two recent Nature Immunology papers, scientists provide insight into how colorectal cancer rewires regulatory T cells, or Treg cells, to promote tumor growth. In that setting, Treg cells switch from suppressing to promoting inflammation, fueling tumor growth. Simultaneously, they protect tumors from attack by T cells.

Khashayarsha Khazaie, Ph.D., a Mayo Clinic scientist; Fotini Gounari, Ph.D., a scientist at The University of Chicago; and Majid Kazemian, Ph.D., a Purdue University researcher, identified key molecules that direct these changes in regulatory T cell functions in colorectal cancer. This knowledge opens a new window to understand how cancer compromises immunity to its advantage, paving the path to better-targeted cancer prevention and treatment.

From left are Khashayarsha Khazaie, Ph.D., a Mayo Clinic scientist; Fotini Gounari, Ph.D., a scientist at The University of Chicago; and Majid Kazemian, Ph.D., a Purdue University researcher. Images were provided by Mayo Clinic, The University of Chicago and Purdue University, respectively.

Out-of-Tune Immune Cells

"The general notion is that the job of Treg cells is to suppress immune responses. But they actually have many different functions and can use these in various combinations under different circumstances in the body," says Dr. Khazaie. "And one such exact circumstance for me is cancer. A single protein called FOXP3 broadly dictates Treg suppressive functions, while others, including ROR-gamma-T, beta-catenin and TCF-1, fine-tune them."

It is a win-win situation for colon cancer.

Regulatory T cells in the colon interact with microbiota and immune cells to produce a healthy level of inflammation that protects against infection. These Treg cells are "tuned" to suppress the immune response by the protein FOXP3, and "fine-tuned" by the proteins ROR-gamma-T, beta-catenin and TCF-1. But colon tumors secrete biological mediators that alter the gut microbiota and properties of Treg cells. Tumor growth causes elevated expression of beta-catenin and lower expression of TCF-1 in Treg cells. In turn, while this makes Treg cells unable to control inflammation, they are better at suppressing T-cells. Image created with BioRender.

Following the Pathway

These studies, the authors say, reveal the cellular and molecular complexity of regulatory T cells. They raises questions about the role of different types of Treg cells in health and disease.

"I am driven to understand what causes disease," says Dr. Khazaie. "We identified multiple molecularly distinct subsets of Treg cells. These subsets responded differently to changes in expression of TCF-1, and to colon cancer in mice."

Of course, he continues, to understand why things go wrong, it helps first to learn how they normally function. And things going right is Dr. Gounari's department.

"I'm interested in understanding why Treg cells are so complex and what each subset does in the normal healthy environment. To understand how things work, you have to tweak them and see what changes," says Dr. Gounari. "It is becoming clear that we can look into the complex molecular pathways and find identifiers that help us understand how normal things work."

And the search for molecular identifiers is where Dr. Kazemian comes into play.

"Complex diseases need complex tools to decipher," says Dr. Kazemian. "Over the past few years, we have created some of these tools that help us understand such complexity."

The team's findings have paved the path for normalizing immunity in cancer to improve cancer prevention and therapy. The knowledge gained is also highly relevant to the success of transplants and the control of autoimmune diseases.

"It is the job of the scientists to go beyond the standard of care, bringing basic and translational research into clinical practice," says Dr. Khazaie. "The ultimate goal is to help patients with debilitating and life-threatening diseases."

Their work appeared in Nature Immunology in April and August.