USF Health, Tampa General study finds colorectal cancer’s immune defenses may begin outside the cancer cell

USF Health researchers, working in collaboration with Tampa General Hospital and Hokkaido University in Japan, have identified a hidden mechanism that enables metastatic colorectal cancer to resist the body's immune defenses, offering a promising target for future therapies for the world's second-leading cause of cancer-related deaths.

The international study, published in the Journal of Experimental & Clinical Cancer Research, found that a biological process long thought to occur primarily inside cancer cells instead appears to play a central role in the environment surrounding metastatic tumors, where it is associated with immune suppression, more advanced disease and poorer patient survival.

In laboratory experiments, researchers blocked two key components of the pathway, allowing healthy killer T cells to return and successfully attack the cancer cells again. The findings could explain why most metastatic colorectal cancers respond poorly to certain immunotherapies and point toward strategies for making those treatments more effective.

"For decades, we have thought of this pathway largely in terms of what happens inside the cancer cell," said Dr. Timothy J. Yeatman, professor of Surgery at the USF Health Morsani College of Medicine, associate center director for Translational Research and Innovation at the TGH Cancer Institute, and senior author of the study. "What we found suggests that much of the important activity is actually happening in the tumor microenvironment, where it creates conditions that prevent the immune system from effectively attacking the cancer."

About thirty years ago, the "rheostat" model proposed that elevated sphingosine-1-phosphate (S1P) promotes tumor cell growth, whereas higher ceramide levels trigger cell death. Under this traditional model, scientists thought that cancer cells used this internal mechanism to control their own fate, turning up S1P to grow uncontrollably or turning down ceramide to avoid dying, just like a physical rheostat, or dimmer switch, controls electrical current by increasing or decreasing resistance.

The new, multi-institute study showed that an important part of that balancing act occurs outside the cancer cells themselves in immune cells called macrophages.

By examining 574 human colon cancer tissue samples through advanced mapping technology, they found that as colorectal cancer spreads, levels of pro-cancer growth lipids (S1P) increased, whereas levels of the cancer cell-killing lipid (ceramide) dropped significantly.

The prevailing theory assumed this chemical balancing act was happening inside the tumor cells. But advanced spatial mapping showed that the molecules that make and receive these "stay alive" signals are concentrated in the surrounding healthy-looking support tissue and specialized immune cells. This creates a state of ongoing, unhealthy inflammation that blocks killer immune cells, preventing them from getting close enough to fight and destroy the tumor.

The researchers also identified a specific three-gene signature that acts as a warning of aggressive cancer. High activity of this gene signature is strongly linked to late-stage cancer, tumors spreading into lymph nodes, lower patient survival rates and poor responses to standard immunotherapy drugs. The lab experiments support further investigation into whether targeting the pathway could alter the immune environment surrounding a tumor and help immune cells function more effectively.

Colorectal cancer remains one of the most challenging cancers to treat, with five-year survival rates of about 14% once the disease spreads. While immune therapies have revolutionized treatment for several cancers, most colorectal tumors at this stage are resistant to these treatments. Understanding why is a major clinical challenge.

The findings suggest that targeting the S1P/S1PR3 pathway could help overcome that resistance and improve the effectiveness of immunotherapy for patients with advanced colorectal cancer.