Telomere length sensitive regulation of interleukin receptor 1 type 1 (IL1R1) by the shelterin protein TRF2 modulates immune signalling in the tumour microenvironment.

Autor:	Mukherjee AK; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Dutta S; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Singh A; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., Sharma S; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Roy SS; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Sengupta A; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Chatterjee M; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., Vinayagamurthy S; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Bagri S; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Khanna D; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., Verma M; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., Soni D; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India., Budharaja A; IIT Delhi, Delhi, India., Bhisade SK; IISER Bhopal, Bhopal, India., Anand V; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.; Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., Perwez A; Integrative and Functional Biology Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., George N; National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India., Faruq M; Academy 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, India., Gupta I; IIT Delhi, Delhi, India.; IISER Bhopal, Bhopal, India., Sabarinathan R; GNR Knowledge Centre for Genome and Informatics, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India., Chowdhury S; Integrative 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, India.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Dec 27; Vol. 13. Date of Electronic Publication: 2024 Dec 27.
DOI:	10.7554/eLife.95106
Abstrakt:	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. Competing Interests: AM, SD, AS, SS, SR, AS, MC, SV, SB, DK, MV, DS, AB, SB, VA, AP, NG, MF, IG, RS, SC No competing interests declared (© 2024, Mukherjee, Dutta, Singh et al.)
Databáze:	MEDLINE
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