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 signal...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/95106 |
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| author | Ananda Kishore Mukherjee Subhajit Dutta Ankita Singh Shalu Sharma Shuvra Shekhar Roy Antara Sengupta Megha Chatterjee Soujanya Vinayagamurthy Sulochana Bagri Divya Khanna Meenakshi Verma Dristhi Soni Anshul Budharaja Sagar Kailasrao Bhisade Vivek Anand Ahmad Perwez Nija George Mohammed Faruq Ishaan Gupta Radhakrishnan Sabarinathan Shantanu Chowdhury |
| author_facet | Ananda Kishore Mukherjee Subhajit Dutta Ankita Singh Shalu Sharma Shuvra Shekhar Roy Antara Sengupta Megha Chatterjee Soujanya Vinayagamurthy Sulochana Bagri Divya Khanna Meenakshi Verma Dristhi Soni Anshul Budharaja Sagar Kailasrao Bhisade Vivek Anand Ahmad Perwez Nija George Mohammed Faruq Ishaan Gupta Radhakrishnan Sabarinathan Shantanu Chowdhury |
| author_sort | Ananda Kishore Mukherjee |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8f17d1dcdb3d4d46a535a0dd2c7399c3 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-8f17d1dcdb3d4d46a535a0dd2c7399c32025-01-07T16:58:17ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.95106Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironmentAnanda Kishore Mukherjee0https://orcid.org/0000-0002-3082-6749Subhajit Dutta1Ankita Singh2Shalu Sharma3Shuvra Shekhar Roy4Antara Sengupta5Megha Chatterjee6Soujanya Vinayagamurthy7https://orcid.org/0000-0003-1465-9925Sulochana Bagri8https://orcid.org/0000-0001-7407-2558Divya Khanna9Meenakshi Verma10Dristhi Soni11Anshul Budharaja12Sagar Kailasrao Bhisade13Vivek Anand14Ahmad Perwez15Nija George16Mohammed Faruq17Ishaan Gupta18Radhakrishnan Sabarinathan19Shantanu Chowdhury20https://orcid.org/0000-0001-7185-8408Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, IndiaIIT Delhi, Delhi, IndiaIISER Bhopal, Bhopal, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaNational Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, IndiaAcademy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIIT Delhi, Delhi, India; IISER Bhopal, Bhopal, IndiaGNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative Biology, New Delhi, IndiaIntegrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India; GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Trivedi School of Biosciences, Ashoka University, Sonepat, IndiaTelomeres 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.https://elifesciences.org/articles/95106telomereTRF2telomeric repeat binding factor 2interleukin-1 signallingtumour macrophagesTNBC |
| spellingShingle | Ananda Kishore Mukherjee Subhajit Dutta Ankita Singh Shalu Sharma Shuvra Shekhar Roy Antara Sengupta Megha Chatterjee Soujanya Vinayagamurthy Sulochana Bagri Divya Khanna Meenakshi Verma Dristhi Soni Anshul Budharaja Sagar Kailasrao Bhisade Vivek Anand Ahmad Perwez Nija George Mohammed Faruq Ishaan Gupta Radhakrishnan Sabarinathan Shantanu Chowdhury Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment eLife telomere TRF2 telomeric repeat binding factor 2 interleukin-1 signalling tumour macrophages TNBC |
| title | Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment |
| title_full | Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment |
| title_fullStr | Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment |
| title_full_unstemmed | Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment |
| title_short | Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment |
| title_sort | telomere length sensitive regulation of interleukin receptor 1 type 1 il1r1 by the shelterin protein trf2 modulates immune signalling in the tumour microenvironment |
| topic | telomere TRF2 telomeric repeat binding factor 2 interleukin-1 signalling tumour macrophages TNBC |
| url | https://elifesciences.org/articles/95106 |
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