Researchers at Memorial Sloan Kettering Cancer Center report that colorectal tumors can contain two major subtypes of regulatory T cells with opposing effects—one associated with restraining tumor growth and another linked to suppressing anti-tumor immunity. The work, published in Immunity, helps explain why higher overall levels of these immune cells have been tied to better outcomes in colorectal cancer and suggests a potential strategy for more selective Treg-targeted therapies.
Colorectal cancer has long posed an immunology puzzle: in many solid tumors, abundant regulatory T (Treg) cells are generally associated with worse outcomes, but colorectal cancers with more Tregs have often been linked to longer survival.
A study from the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK), published in the journal Immunity, reports an explanation: tumor-associated Tregs in colorectal cancer can be separated into two main groups with opposing functions. One subset produces the cytokine interleukin-10 (IL-10), while the other does not.
The researchers focused on the most common form of colorectal cancer—microsatellite stable (MSS) tumors with proficient mismatch repair (MMRp)—which MSK says represents about 80% to 85% of cases and typically does not respond well to checkpoint inhibitor immunotherapies. By contrast, MSK notes that tumors with high microsatellite instability (MSI-H) and mismatch repair deficiency (MMRd) can often respond strongly to immunotherapy.
Using a mouse model developed at MSK that the institution says closely mirrors key features of human colorectal tumors, the team performed experiments in which each Treg subset was selectively removed. MSK reports that IL-10–positive Tregs tended to be more common in healthy tissue near the tumor and slowed tumor growth by reducing activity of Th17 cells, which produce interleukin-17 (IL-17)—described in the release as a tumor growth signal. When IL-10–positive Tregs were removed, tumors grew faster.
In contrast, the IL-10–negative Treg subset was described as being mainly found within tumors and as suppressing anti-cancer immune defenders—especially CD8+ T cells. When the IL-10–negative subset was eliminated, tumors became smaller.
MSK says the team also examined human colorectal cancer tumor samples and again identified IL-10–positive and IL-10–negative Treg populations. In an outcomes analysis of more than 100 colorectal cancer patients, higher levels of IL-10–positive Tregs were associated with longer survival, while higher levels of IL-10–negative Tregs were associated with poorer outcomes.
The findings also point to a potential route for more selective immunotherapy. MSK reports that the IL-10–negative, immunosuppressive Tregs expressed high levels of CCR8, a protein that has been proposed as a target for antibody-based depletion of tumor Tregs. In the MSK account, multiple clinical trials are testing CCR8-depleting antibodies at MSK and elsewhere, both alone and in combination with existing immunotherapies.
Looking beyond colorectal cancer, the researchers analyzed a large dataset of T cells across 16 cancer types and reported seeing similar IL-10–based divisions of Tregs in several cancers arising in barrier tissues, including the skin and the linings of the mouth, throat, and stomach.
The study also reports a different pattern in colorectal cancer that has metastasized to the liver. In that setting, MSK says IL-10–negative Tregs were more dominant, and removing all Tregs—rather than selectively targeting one subset—caused metastatic tumors to shrink, underscoring the need for treatment approaches tailored to disease stage and tissue context.
MSK framed the work as building on more than two decades of research by Alexander Rudensky on Treg biology and immune tolerance, and suggested that distinguishing between protective and harmful Treg subsets could help guide more precise immunotherapy strategies for colorectal cancer and potentially other tumor types.
