According to the American Cancer Society, colorectal cancer is the second leading cause of cancer death. Enrichment of regulatory T cells (T-regs) in solid cancers is generally associated with poor prognosis because these cells dampen the immune system’s ability to fight against a tumor. However, colorectal cancer stands out as an exception, as high density of T-regs in colorectal tumors is associated with improved survival. The mechanism for these improved outcomes has not been understood.
In a new study published in Immunity titled, “Opposing functions of distinct regulatory T cell subsets in colorectal cancer,” researchers from Memorial Sloan Kettering Cancer Center (MSK) have identified two distinct tumoral T-reg subsets with differential Il10 expression in colorectal cancer. The results could improve immunotherapy treatment for patients with cancers that affect tissues such as the skin and the lining of the stomach, mouth, and throat.
“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 T-reg cells that play opposing roles—one restrains tumor growth, while the other fuels it,” said Alexander Rudensky, PhD, co-corresponding author of the study, Howard Hughes Medical Institute (HHMI) Investigator, and chair of the Immunology Program at MSK. “It’s these beneficial T-reg cells that make the difference, and this underscores the need for selective approaches.”
The researchers focused on microsatellite stable (MSS) with proficient mismatch repair (MMRp), a type of colorectal cancer that accounts for 80% to 85% of all colorectal cancers. The DNA of these tumors is relatively stable, leading these cancers to be largely resistant to checkpoint inhibitor immunotherapies.
The team employed a mouse model that recapitulated common mutations, behaviors, and immune cell composition of human colorectal cancer. Results showed that IL-10-positive T-regs dampen the activity of Th17 cells, which produce interleukin 17 (IL-17) and acts as a growth factor for the tumor. Tumor growth accelerated when IL-10-positive cells were removed.
In contrast, IL-10-negative T-regs, suppress immune defenders, such as CD8+ T cells with strong anti-cancer capabilities. This subtype of T-regs is largely found within the tumor itself. The researchers validated their laboratory findings using tumor samples from 100 patients with colorectal cancer.
“This research shows how important these positive cells are,” said Xiao Huang, PhD, first author of the study and research associate at MSK. “And it highlights the need to develop therapies that can selectively eliminate the harmful T-regs while preserving the helpful ones.”
Rudensky says the research points to opportunities to improve outcomes for the majority of colorectal cancer patients. Notably, results showed that the IL-10-negative cells expressed high levels of CCR8.
“This idea of using CCR8-depleting antibodies, which was pioneered at MSK, is the main target of global efforts to bring regulatory T cell–based immunotherapy to the clinic,” said Rudensky.
Numerous clinical trials are underway at MSK to test the approach as a standalone treatment and in combination with other immunotherapies. The researchers also suggest that approaches that selectively target IL-10-negative cells in colorectal cancer may be effective against other barrier-tissue cancers.
