A recent study by researchers at the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK) has provided new insights into why regulatory T (Treg) cells are linked to better outcomes in colorectal cancer, contrary to their role in most other solid tumors. The findings were published on December 15 in Immunity.
In most cancers, a high number of Treg cells is associated with poorer patient outcomes because these cells suppress the immune system’s ability to fight tumors. However, colorectal cancer has been an exception, with higher densities of Treg cells correlating with improved survival rates. The reasons for this paradox have remained unclear until now.
The research team discovered that it is not just the quantity but the type of Treg cell present in colorectal tumors that matters. "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," said Alexander Rudensky, PhD, co-senior author 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."
The study was led by Xiao Huang, PhD; Dan Feng, MD, PhD; and Sneha Mitra, PhD. Christina Leslie, PhD served as another senior author.
Colorectal cancer remains a major health concern and is currently the second leading cause of cancer death when considering both men and women together.
Researchers focused on microsatellite stable (MSS) colorectal cancers with proficient mismatch repair (MMRp), which represent 80% to 85% of all cases and are typically resistant to checkpoint inhibitor immunotherapies. Previous work at MSK had shown that checkpoint inhibitors can be effective for tumors with high microsatellite instability (MSI-H) and mismatch repair deficiency (MMRd).
Using a mouse model developed at MSK that mirrors human colorectal cancer mutations and immune cell makeup, scientists identified two types of Treg cells: those producing interleukin-10 (IL-10) and those that do not. Experiments showed that IL-10-positive Tregs were associated with longer patient survival, while IL-10-negative ones correlated with worse outcomes.
"This research shows how important these positive cells are," Dr. Huang said. "And it highlights the need to develop therapies that can selectively eliminate the harmful Tregs while preserving the helpful ones."
Further analysis revealed that IL-10-negative Tregs express high levels of CCR8 protein—a finding consistent with earlier research from Dr. Rudensky’s lab involving breast cancer and other tumor types. This suggests harmful Tregs could potentially be targeted using antibodies against CCR8 without affecting beneficial ones.
"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," Dr. Rudensky said.
Clinical trials are underway at MSK and elsewhere testing this approach alone or combined with other immunotherapies.
Researchers also examined data from 16 different cancer types and found similar distinctions between IL-10-positive and negative Tregs in several cancers affecting barrier tissues such as skin and mucosal linings.
"What these tissues have in common is that immune cells play a critical role in constantly defending and repairing them as they're exposed to microbes and environmental stresses," said Dr. Mitra.
The study further noted differences between primary colorectal tumors and those metastasized to the liver; metastatic sites contained more IL-10-negative than positive cells—indicating therapeutic strategies may need adjustment depending on tumor location.
Additional contributors included Emma Andretta, Nima Hooshdaran, Aazam Ghelani, Eric Wang, Joe Frost, Victoria Lawless, Aparna Vancheswaran, Qingwen Jiang, Cheryl Mai, and Karuna Ganesh. The Integrated Genomics Operation and Single Cell Research Initiative at MSK supported this work.
Funding came from multiple sources including the National Cancer Institute (P30 CA008748; U54 CA274492; T32 CA009512), National Institute of Allergy and Infectious Diseases (AI034206), Ludwig Center for Cancer Immunotherapy at MSK, Howard Hughes Medical Institute, Cancer Research Institute, and Marie-Joseé Kravis Fellowship in Quantitative Biology.
Dr. Rudensky disclosed advisory roles or equity interests in several biotechnology companies including Sonoma Biotherapeutics; RAPT Therapeutics; Coherus Oncology; Santa Ana Bio; Odyssey Therapeutics; Nilo Therapeutics; Amgen; BioInvent; Vedanta Biosciences; AbbVie; he also serves editorial roles for scientific journals Immunity and Journal of Experimental Medicine.
Both Drs. Rudensky and Plitas are inventors on patents held by MSK related to CCR8-based therapies targeting tumoral Treg cells.
