By Gilang Cahya 
In the complex landscape of cancer immunology, regulatory T (Treg) cells have long been recognized as formidable adversaries. Typically functioning as the immune system’s brakes, these cells are often found in abundance within solid tumors, where they dampen the body’s natural defenses, leading to poorer patient outcomes across a spectrum of malignancies. However, colorectal cancer has presented a persistent and perplexing exception to this rule. For years, scientific inquiry has been captivated by the observation that tumors with a higher infiltration of Treg cells in this specific cancer are frequently associated with improved survival rates, a stark contrast to the prevailing understanding. This apparent anomaly has now been illuminated by groundbreaking research from the Sloan Kettering Institute at Memorial Sloan Kettering Cancer Center (MSK), offering a profound explanation that could reshape the future of colorectal cancer immunotherapy.
The pivotal discovery, published in the esteemed scientific journal Immunity, centers on the intricate heterogeneity of Treg cells. Rather than a monolithic entity, researchers have found that Treg populations are not uniform in their function. The crucial determinant of their impact on colorectal cancer appears not to be their sheer number, but rather their specific subtype and the distinct roles they play. This nuanced understanding challenges decades of established dogma and opens new avenues for therapeutic intervention.
"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," explained Dr. Alexander Rudensky, PhD, co-senior author of the study 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." Dr. Rudensky, a globally recognized authority on regulatory T cells with over two decades of dedicated research, has been instrumental in establishing the fundamental concept of Treg cells maintaining "immune tolerance"—the critical ability of the immune system to distinguish between harmful pathogens and the body’s own tissues, beneficial microbes, and innocuous substances like food. His lab’s extensive work has meticulously mapped the genesis, function, and influence of Treg cells on cancer development, laying the essential groundwork for this latest breakthrough.
A Decades-Long Pursuit Culminates in a Paradigm Shift
The ambitious research initiative was spearheaded by a collaborative effort, with Dr. Xiao Huang, PhD, a postdoctoral researcher in the Rudensky Lab, Dr. Dan Feng, MD, PhD, a former MSK Medical Oncology fellow now at the Icahn School of Medicine at Mount Sinai, and Dr. Sneha Mitra, PhD, a postdoctoral researcher in the lab of computational biologist Dr. Christina Leslie, PhD, serving as co-first authors. The study represents a significant culmination of Dr. Rudensky’s enduring commitment to unraveling the complexities of the immune system’s interaction with cancer.
Colorectal cancer, a significant global health challenge responsible for the second-highest number of cancer-related deaths when men and women are considered together according to the American Cancer Society, provided the specific focus for this investigation. The researchers concentrated their efforts on the most prevalent form of the disease, accounting for approximately 80% to 85% of all colorectal cancers. This particular subtype is characterized by microsatellite stability (MSS) and proficient mismatch repair (MMRp), indicating a relatively stable DNA genome. Crucially, these MSS/MMRp tumors have historically demonstrated a poor response to current checkpoint inhibitor immunotherapies, a stark contrast to their highly effective treatment of the opposite tumor type: cancers with high microsatellite instability (MSI-H) and mismatch repair deficiency (MMRd). These latter cancers can often be successfully managed with immunotherapy alone, frequently sparing patients the rigors of surgery, chemotherapy, and radiation. This disparity in treatment efficacy further underscored the need to understand the unique immunological microenvironment of MSS/MMRp colorectal cancers.
Unmasking the Dual Nature of Treg Cells: A Tale of Two Subtypes
To meticulously dissect the immunological differences that define MSS/MMRp colorectal cancers, the research team employed a sophisticated mouse model. This model was specifically engineered at MSK to faithfully replicate the genetic alterations, behavioral characteristics, and immune milieu of human colorectal tumors. Through extensive experimentation within this model, the scientists identified two primary subgroups of tumor-associated Treg cells, distinguished by their production of a key signaling molecule, or cytokine, known as interleukin-10 (IL-10).
The impact of each subgroup on tumor progression was then rigorously assessed by selectively eliminating them. This detailed experimental approach revealed starkly contrasting effects. Treg cells that produce IL-10, designated as IL-10-positive Treg cells, were found to actively restrain tumor growth. Their mechanism of action involves suppressing the activity of another critical immune cell type, Th17 cells, which produce interleukin 17 (IL-17). IL-17, in turn, acts as a growth stimulant for tumors. These protective IL-10-positive Treg cells were predominantly observed in the healthy tissue surrounding the tumor. The experimental removal of these beneficial cells led to accelerated tumor growth, reinforcing their anti-tumorigenic role.
Conversely, Treg cells that do not produce IL-10, termed IL-10-negative Treg cells, exhibited an opposing and detrimental effect. These cells function by suppressing potent immune defenders, most notably CD8+ T cells, which are renowned for their cancer-fighting capabilities. This deleterious subtype was found to be concentrated primarily within the tumor mass itself. The experimental elimination of these IL-10-negative Treg cells resulted in a significant reduction in tumor size, unequivocally demonstrating their pro-tumorigenic influence.
Human Data Validates In Vivo Findings: A Glimmer of Hope for Patients
The findings derived from the mouse model were not confined to preclinical observations. The research team meticulously validated these discoveries using a comprehensive collection of tumor samples from human colorectal cancer patients. Within these patient-derived samples, the researchers consistently identified the same two distinct populations of Treg cells: the beneficial IL-10-positive subtype and the detrimental IL-10-negative subtype.
Furthermore, an analysis of survival data from over 100 colorectal cancer patients provided compelling clinical correlation. Individuals whose tumors harbored higher levels of the beneficial IL-10-positive Treg cells exhibited significantly longer survival periods. Conversely, patients with a greater abundance of the harmful IL-10-negative Treg cells in their tumors experienced poorer clinical outcomes. "This research shows how important these positive cells are," stated Dr. Huang. "And it highlights the need to develop therapies that can selectively eliminate the harmful Tregs while preserving the helpful ones." This critical distinction between the two Treg subtypes offers a tangible pathway toward more effective and less toxic treatments.
Targeting CCR8: A Novel Therapeutic Strategy Emerges
The profound insights gleaned from this study point towards a promising therapeutic strategy for the vast majority of colorectal cancer patients. Dr. Rudensky, who also holds an Investigator position at the Howard Hughes Medical Institute, highlighted that the IL-10-negative Treg cells, the primary drivers of immune suppression and predominantly located within the tumor, express high levels of a specific protein receptor known as CCR8.
This observation is particularly significant given prior foundational work from Dr. Rudensky’s lab, led by breast cancer surgeon Dr. George Plitas, MD. That earlier research had established that CCR8 is also highly expressed on tumor Treg cells in breast cancer and a wide array of other human cancers. This prior investigation had posited the potential utility of antibodies designed to selectively target and eliminate these detrimental Treg cells, thereby unleashing the body’s own immune system to more effectively combat tumors while sparing the beneficial Treg cell populations. "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 remarked, underscoring the broad applicability and significance of this approach.
The implications of this research are far-reaching. The current landscape of cancer immunotherapy is actively exploring this CCR8-targeting strategy. Multiple clinical trials are already underway at MSK and other leading institutions, investigating the efficacy of CCR8-depleting antibodies both as standalone treatments and in combination with existing immunotherapies. The new study from MSK significantly strengthens the scientific rationale for employing this targeted approach in colorectal cancer, and potentially across a wider range of malignancies.
Echoes in Other Cancers: A Universal Immune Phenomenon?
The researchers extended their investigation beyond colorectal cancer, analyzing a substantial dataset of T cells from 16 distinct cancer types. Their objective was to ascertain whether the observed immune patterns—the presence of distinct IL-10-producing and non-producing Treg populations—were replicated in other malignancies. The findings revealed striking similarities in several cancers affecting the skin, as well as the mucosal linings of the mouth, throat, and stomach.
Dr. Mitra, who spearheaded the complex data analysis and is jointly mentored by Dr. Leslie and Dr. Rudensky, commented on the commonalities of these tissues: "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." This suggests that therapies designed to selectively eliminate the detrimental IL-10-negative Treg cells in colorectal cancer might also prove effective against cancers originating in these similarly exposed "barrier tissues."
Metastatic Disease Presents a Different Immunological Challenge
The study also delved into the immunological microenvironment of metastatic colorectal cancer, specifically examining tumors that had spread to the liver. In these advanced metastatic lesions, a markedly different immune landscape emerged. Here, the detrimental IL-10-negative Treg cells significantly outnumbered their beneficial IL-10-positive counterparts. Crucially, in this metastatic context, the experimental removal of all Treg cells, rather than a selective depletion, led to the shrinkage of metastatic tumors. This finding underscores the critical need for treatment strategies that are tailored not only to the specific tissue of origin but also to the stage of the disease. The complex interplay between Treg subtypes and their impact on tumor growth can shift dramatically as cancer progresses.
Funding and Disclosures
The research was supported by substantial funding from various national and institutional bodies, including the National Cancer Institute (P30 CA008748, U54 CA274492, T32 CA009512), the National Institute of Allergy and Infectious Diseases (AI034206), the Ludwig Center for Cancer Immunotherapy at MSK, the Howard Hughes Medical Institute, the Cancer Research Institute, and a Marie-José Kravis Fellowship in Quantitative Biology. Key contributions were also made by MSK’s Integrated Genomics Operation and Single Cell Research Initiative.
Dr. Rudensky’s extensive involvement in the field is reflected in his advisory roles and equity in several biotech companies, including Sonoma Biotherapeutics, RAPT Therapeutics, Coherus Oncology, Santa Ana Bio, Odyssey Therapeutics, and Nilo Therapeutics. He also serves on the scientific advisory boards of Amgen, BioInvent, and Vedanta Biosciences, has consulted for AbbVie, and holds editorial positions with leading scientific journals, including the Journal of Experimental Medicine and Immunity. Notably, Dr. Rudensky and Dr. Plitas are named inventors on patents and patent applications held by MSK related to CCR8-based therapeutic depletion of tumoral Treg cells and novel antibodies targeting CCR8. These disclosures highlight the potential for significant translation of this research into clinical practice.
