Related Experiment Video
Updated: Oct 23, 2025
Establishment of a Co-culture System of Patient-Derived Colorectal Tumor Organoids and Tumor-Infiltrating Lymphocytes (TILs)
Published on: June 27, 2025
Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer
Jeremy Goc1, Mengze Lv1, Nicholas J Bessman1
1Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
Abstract:
Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.
Insights
Group 3 innate lymphoid cells (ILC3s) are crucial for anti-cancer immunity. In colorectal cancer (CRC), ILC3 dysfunction impairs gut immunity, promoting tumor growth and resistance to immunotherapy.
Area of Science:
- Immunology
- Oncology
- Microbiome research
Background:
- Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity and inflammation.
- The specific role of ILC3s in the context of colorectal cancer (CRC) pathogenesis and progression is not well understood.
- Alterations in ILC3 populations and their interactions with other immune cells may influence cancer development.
Purpose of the Study:
- To investigate the role of ILC3s in colorectal cancer (CRC).
- To elucidate the mechanisms by which ILC3s influence the tumor microenvironment and anti-tumor immunity.
- To determine the impact of ILC3 dysfunction on immunotherapy response.
Main Methods:
- Analysis of ILC3 frequencies and plasticity in CRC patient samples.
- Evaluation of ILC3-T cell interactions via major histocompatibility complex class II (MHCII) in mouse models.
- Assessment of microbiota colonization and type-1 immunity induction.
- Testing the efficacy of anti-PD-1 immunotherapy in relevant mouse models.
- Functional studies involving transfer of microbiota from human CRC patients to mice.
Main Results:
- Colorectal cancer (CRC) is associated with reduced frequencies and increased plasticity of ILC3s, leading to an imbalance with T cells.
- A critical dialog between ILC3s and T cells mediated by MHCII is essential for maintaining protective microbiota and type-1 immunity.
- Mice lacking ILC3-specific MHCII exhibit invasive CRC and resistance to anti-PD-1 immunotherapy.
- Human CRC patients with dysregulated ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness.
Conclusions:
- Group 3 innate lymphoid cells (ILC3s) play a protective role in cancer, particularly in colorectal cancer (CRC).
- Disruption of ILC3s in CRC leads to impaired adaptive immunity, promoting tumor progression and immunotherapy resistance.
- Restoring ILC3 function and associated microbiota-induced type-1 immunity may represent a therapeutic strategy for CRC.
More Related Videos
Related Concept Videos
01:24T Cell Types and Functions
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:12Role Of Notch Signalling In Intestinal Stem Cell Renewal
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...