Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment
Telomeres are crucial for cancer progression. Immune signalling in the tumour microenvironment has been shown to be very important in cancer prognosis. However, the mechanisms by which telomeres might affect tumour immune response remain poorly understood. Here, we observed that interleukin-1 signalling is telomere-length dependent in cancer cells. Mechanistically, non-telomeric TRF2 (telomeric repeat binding factor 2) binding at the IL-1-receptor type-1 (IL1R1) promoter was found to be affected by telomere length. Enhanced TRF2 binding at the IL1R1 promoter in cells with short telomeres directly recruited the histone-acetyl-transferase (HAT) p300, and consequent H3K27 acetylation activated IL1R1. This altered NF-kappa B signalling and affected downstream cytokines like IL6, IL8, and TNF . Further, IL1R1 expression was telomere-sensitive in triple-negative breast cancer (TNBC) clinical samples. Infiltration of tumour-associated macrophages (TAM) was also sensitive to the length of tumour cell telomeres and highly correlated with IL1R1 expression. The use of both IL1 Receptor antagonist (IL1RA) and IL1R1 targeting ligands could abrogate M2 macrophage infiltration in TNBC tumour organoids. In summary, using TNBC cancer tissue (>90 patients), tumour-derived organoids, cancer cells, and xenograft tumours with either long or short telomeres, we uncovered a heretofore undeciphered function of telomeres in modulating IL1 signalling and tumour immunity.
Authors
- Anshul Budharaja
- Soujanya Vinayagamurthy (ORCID: https://orcid.org/0000-0003-1465-9925)
- Sagar Kailasrao Bhisade
- Megha Chatterjee (ORCID: https://orcid.org/0009-0005-7449-2989)
- Radhakrishnan Sabarinathan (ORCID: https://orcid.org/0000-0001-8916-3954)
- Ishaan Gupta (ORCID: https://orcid.org/0000-0001-8934-9919)
- Ahmad Perwez (ORCID: https://orcid.org/0000-0002-8203-5631)
- Antara Sengupta (ORCID: https://orcid.org/0000-0002-0974-9961)
- Dristhi Soni
- Meenakshi Verma (ORCID: https://orcid.org/0000-0003-0107-7539)
- Mohammed Faruq (ORCID: https://orcid.org/0000-0001-8278-8396)
- Shalu Sharma (ORCID: https://orcid.org/0000-0002-0443-3650)
- Shantanu Chowdhury (ORCID: https://orcid.org/0000-0001-7185-8408)
- Subhajit Dutta (ORCID: https://orcid.org/0000-0003-2390-7492)
- Shuvra Shekhar Roy (ORCID: https://orcid.org/0000-0001-6005-2767)
- Sulochana Bagri (ORCID: https://orcid.org/0000-0001-7407-2558)
- Vivek Anand (ORCID: https://orcid.org/0009-0005-6777-7361)
- Ananda Kishore Mukherjee (ORCID: https://orcid.org/0000-0002-3082-6749)
- Ankita Singh (ORCID: https://orcid.org/0009-0000-7608-6347)
- Divya Khanna (ORCID: https://orcid.org/0000-0002-0832-2413)
- Nija George
Institutions
- Tata Institute of Fundamental Research (IN)
- Institute of Genomics and Integrative Biology (IN)
- National Centre for Biological Sciences (IN)
- Indian Institute of Science Education and Research, Bhopal (IN)
- Ashoka University (IN)
- Indian Institute of Technology Delhi (IN)
- Academy of Scientific and Innovative Research (IN)
Publication Details
- Journal
- eLife
- Published
- 2024-12-27
- DOI
- https://doi.org/10.7554/elife.95106.3
- Citations
- 1
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.33
Funders
- Council for Scientific and Industrial Research, South Africa
- Tata Institute of Fundamental Research
- Department of Biotechnology, Ministry of Science and Technology, India
- The Wellcome Trust DBT India Alliance
- National Centre for Biological Sciences