Mystery Solved: Scientists Discover Why Colorectal Cancer Defies Immune System Rules
janrinok writes:
Colorectal cancer breaks the usual immune rules, with certain regulatory T cells linked to improved survival.
In many solid tumors, having a large number of regulatory T (Treg) cells is linked to worse outcomes. These cells can weaken the immune system's ability to recognize and attack cancer.
Colorectal cancer is an unusual exception. In this disease, tumors packed with Treg cells are actually tied to better survival, even though researchers have not fully understood the reason.
A new study from the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK) sheds light on this contradiction. The findings suggest a path toward improving immunotherapy for most people with colorectal cancer, and they may also apply to cancers that develop in tissues such as the skin and the lining of the stomach, mouth, and throat.
According to results published December 15 in Immunity, a leading immunology journal, the key factor is not simply how many Treg cells are present, but which kinds of Treg cells are in the tumor.
"Instead of the regulatory T cells promoting tumor growth, as they do in most cancers, in colorectal cancer we discovered there are actually two distinct subtypes of Treg cells that play opposing roles - one restrains tumor growth, while the other fuels it," says Alexander Rudensky, PhD, co-senior author of the study and chair of the Immunology Program at MSK. "It's these beneficial Treg cells that make the difference, and this underscores the need for selective approaches."
Colorectal cancer is the second leading cause of cancer death when numbers for men and women are combined, according to the American Cancer Society.
For this study, the researchers focused on a type of colorectal cancer that accounts for 80% to 85% of all colorectal cancers - microsatellite stable (MSS) with proficient mismatch repair (MMRp), meaning the tumors' DNA is relatively stable. These cancers are largely resistant to checkpoint inhibitor immunotherapies.
Here the team employed an MSK-developed mouse model that accurately recreates the common mutations, behaviors, and immune cell composition of human colorectal cancer. They found that the regulatory T cells associated with the cancer are split between two types: Cells that make a signaling molecule (cytokine) called interleukin-10 (IL-10) and cells that don't.
Through a series of sophisticated experiments that selectively eliminated each type of cell, the researchers discovered:
- IL-10-positive Tregs help hold tumor growth in check. They work by dampening the activity of a different type of T cell, called Th17 cells - these produce interleukin 17 (IL-17), which acts as a growth factor for the tumor. They're more abundant in healthy tissue adjacent to a tumor.
- When IL-10-positive cells were removed, tumor growth accelerated.
- IL-10-negative Tregs, on the other hand, suppress immune defenders - especially CD8+ T cells with strong anti-cancer capabilities. This subtype of Tregs is largely found within the tumor itself.
- When IL-10-negative cells were removed, the tumors shrank.
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