Distinct Treg Cell Subtypes Offer new Hope for Colorectal Cancer Immunotherapy
A groundbreaking study from Memorial Sloan Kettering Cancer Center (MSK) has revealed a surprising complexity within regulatory T cells (Treg cells) – immune cells that typically suppress the body’s ability to fight cancer – offering a potential new avenue for improving immunotherapy in colorectal cancer and possibly other solid tumors. Published in the journal Immunity, the research demonstrates that not all Treg cells are created equal, with distinct subtypes playing opposing roles in tumor advancement.
colorectal cancer, the second leading cause of cancer-related death in the United States according to the American Cancer Society, has long presented a puzzling anomaly in cancer research. While high levels of Treg cells are generally associated with poorer outcomes in most solid tumors, patients with colorectal cancer often exhibit longer survival rates when their tumors contain a greater number of these cells. For years, scientists have struggled to reconcile this counterintuitive observation.
Now, researchers at MSK believe they have found the answer. “Rather 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,” explained a senior researcher involved in the study. “It’s these beneficial Treg cells that make the difference, and this underscores the need for selective approaches.”
Decades of Research Pave the way for Breakthrough
The findings are the culmination of over 20 years of research led by Alexander Rudensky,PhD,chair of the Immunology Program at MSK,and a leading expert in Treg cell biology. Dr. Rudensky’s earlier work established the critical role of Treg cells in maintaining “immune tolerance,” preventing the immune system from attacking the body’s own tissues. his lab has since mapped out the intricate mechanisms governing Treg cell creation, function, and influence on cancer progression. Dr. rudensky is supported by the Ludwig Center for Cancer Immunotherapy at MSK, the Howard Hughes Medical Institute, the Cancer Research Institute, and a Marie-Joseé Kravis Fellowship in Quantitative Biology.
The current study, spearheaded by Xiao Huang, PhD, Dan Feng, MD, PhD, and Sneha Mitra, PhD, focused on the most common form of colorectal cancer – those that are microsatellite stable (MSS) with proficient mismatch repair (MMRp). These tumors, representing 80% to 85% of all colorectal cancer cases, typically do not respond well to existing checkpoint inhibitor immunotherapies.However, research at MSK has shown that checkpoint inhibitors are highly effective against tumors with high microsatellite instability (MSI-H) and mismatch repair deficiency (MMRd), often allowing patients to avoid more aggressive treatments like surgery, chemotherapy, and radiation.
Two Faces of Treg Cells: Opposing Effects on Tumor Growth
To unravel the complexities of Treg cell behavior in colorectal cancer, the research team utilized a mouse model closely mirroring the genetic and immunological characteristics of human colorectal tumors. Their investigation revealed that tumor-associated Treg cells fall into two primary groups: those that produce interleukin-10 (IL-10) and those that do not.
Detailed experiments demonstrated that IL-10-positive Treg cells actively slow tumor growth. They achieve this by suppressing the activity of Th17 cells,another type of immune cell that produces interleukin 17 (IL-17),a known growth signal for tumors. These protective Treg cells are predominantly found in healthy tissue surrounding the tumor.Removing IL-10-positive Treg cells resulted in accelerated tumor growth.
Conversely, IL-10-negative Treg cells were found to promote tumor growth by supp
