For years, scientists have been puzzled by a counterintuitive trend in colorectal cancer: tumors with more regulatory T cells (Tregs) often correlate with better patient survival. Unlike most cancers where Tregs suppress the immune response and promote growth, colorectal cancer appears to operate differently. Now, a new study from Memorial Sloan Kettering Cancer Center (MSK) reveals that not all Tregs are created equal – and understanding this distinction could unlock more effective immunotherapies.
The Two Faces of Tregs
The research, published in Immunity, demonstrates that colorectal tumors harbor two distinct types of Tregs: one that fuels growth and one that restrains it. The key lies in a signaling molecule called interleukin-10 (IL-10).
“Instead of 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,” explains Dr. Alexander Rudensky, chair of the Immunology Program at MSK. This discovery highlights the need for targeted therapies that selectively eliminate harmful Tregs while preserving the beneficial ones.
Decades of Research Converge
This breakthrough builds upon over 20 years of Dr. Rudensky’s work on Tregs, establishing that these cells maintain “immune tolerance” by preventing attacks on the body’s own cells. His lab has mapped how Tregs are created, how they function, and their complex role in cancer development. The current study leverages this foundation to finally explain the paradoxical behavior observed in colorectal cancer.
The Most Common Type: MSS/MMRp
The study focused on the most prevalent form of colorectal cancer (80–85% of cases) – microsatellite stable (MSS) with proficient mismatch repair (MMRp). This type typically resists standard checkpoint inhibitor immunotherapies, making the new findings particularly relevant.
In contrast, highly unstable tumors (MSI-H/MMRd) do respond well to immunotherapy, often avoiding the need for surgery, chemotherapy, or radiation. This research aims to bridge the gap and improve outcomes for the more common MSS/MMRp cancers.
IL-10: The Protective Signal
Researchers used a mouse model mirroring human colorectal tumors to identify the two Treg subtypes. The IL-10-positive Tregs slow tumor growth by suppressing Th17 cells, which produce a growth-promoting signal. These protective Tregs are commonly found in healthy tissue surrounding the tumor. Removing them accelerates tumor progression.
The other subtype, IL-10-negative Tregs, suppresses cancer-fighting CD8+ T cells, allowing tumors to thrive. These harmful Tregs are concentrated within the tumor itself. Eliminating them shrinks tumors.
Patient Data Confirms the Findings
Analysis of tumor samples from over 100 colorectal cancer patients confirmed these results. Higher levels of IL-10-positive Tregs were associated with longer survival, while increased IL-10-negative Tregs predicted poorer outcomes. This correlation reinforces the need to target the harmful Tregs selectively.
Targeting CCR8: A Promising Strategy
The study identifies a potential therapeutic target: the CCR8 protein, highly expressed on IL-10-negative Tregs. Antibodies that deplete these cells have been in development at MSK for years, with multiple clinical trials underway.
“This idea of using CCR8-depleting antibodies… is the main target of global efforts to bring regulatory T cell-based immunotherapy to the clinic,” Dr. Rudensky notes.
Beyond Colorectal Cancer?
Similar immune patterns were observed in cancers affecting the skin, mouth, throat, and stomach – tissues constantly exposed to microbes and environmental stress. Therapies designed for colorectal cancer may also prove effective against these other cancers.
However, metastatic tumors showed a different immune balance, with IL-10-negative Tregs dominating. In these cases, removing all Tregs led to tumor shrinkage, suggesting that treatment strategies must be tailored to the disease stage and tissue type.
This research underscores that the immune system in colorectal cancer is far from monolithic. By understanding the opposing roles of different Treg subtypes, scientists are one step closer to developing immunotherapies that work for more patients.
