Quantity of Immune Cells Predict Response to Immunotherapy in Cancer

Salgado, Roberto; Gevaert, Thomas

doi:10.1016/j.eclinm.2021.101170

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…Major advances show how immune cells including tumour-infiltrating-lymphocytes (TIL), tumourassociated-macrophages (TAM), natural-killer and dendritic cells impact cancer progression (Binnewies et al, 2018 ;Gonzalez et al, 2018 ;Jochems and Schlom, 2011 ;Salgado and Gevaert, 2021 ). TAMs -typically M2 macrophage-like -predominantly promote immunosuppressive tumour microenvironment (TME) through secretion of anti-inflammatory cytokines (Burkholder et al, 2014 ;Cassetta et al, 2016 ;DeNardo and Ruffell, 2019 ;Gonzalez et al, 2018 ;Pittet et al, 2022 ;SD et al, 2020), implicating the role of TAMs in aggressive tumour growth (Hu et al, 2015 ;Pittet et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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

Mukherjee,

Dutta,

Singh

et al. 2024

eLife

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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.

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Section: Introductionmentioning

confidence: 99%

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

Mukherjee,

Dutta,

Singh

et al. 2024

eLife

View full text Add to dashboard Cite

show abstract

“…Major advances show how immune cells including tumour-infiltrating-lymphocytes (TIL), tumourassociated-macrophages (TAM), natural-killer and dendritic cells impact cancer progression (Binnewies et al, 2018;Gonzalez et al, 2018;Jochems and Schlom, 2011;Salgado and Gevaert, 2021). TAMs -typically M2 macrophage-likepredominantly promote immunosuppressive tumour microenvironment (TME) through secretion of anti-inflammatory cytokines (Burkholder et al, 2014;Cassetta et al, 2016;DeNardo and Ruffell, 2019;Gonzalez et al, 2018;Pittet et al, 2022;SD et al, 2020), implicating the role of TAMs in aggressive tumour growth (Hu et al, 2015;Pittet et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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

Mukherjee

Singh

Sharma

et al. 2021

Preprint

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The role of telomeres in sustained tumor growth is well understood. However, mechanisms of how telomeres might impact the tumor microenvironment (TME) are not clear. Upon examining tumor associated macrophages (TAMs) in 94 hormone-negative (triple-negative) breast cancer (TNBC) cases we found infiltration of TAMs to be telomere sensitive: Tumors with relatively short telomeres had higher abundance of TAM and vice versa. This observation was replicated across TNBC clinical tissue, patient-derived organoids, tumor xenografts and cancer cells with long/short telomeres. Mechanistically, we demonstrate that non-telomeric binding of TRF2, a telomere-repeat-binding-factor; at the interleukin receptor IL1R1 promoter directly activates IL1R1 through recruitment of the histone-acetyl-transferase p300 and consequent H3K27 acetylation. Interleukin-1signaling could be induced in TRF2-high cells through ligands IL1A/B, but not TNFα, and abrogated by the receptor antagonist IL1RA, supporting specificity of the TRF2-IL1R1axis. TRF2 binding at the IL1R1 promoter was mediated by G-quadruplex motifs and was sensitive to telomere length – thereby establishing telomere-length-dependent regulation of IL1R1 and IL1-mediated TAM infiltration in cancers. Our results reveal a heretofore unknown function of telomeres in interleukin signaling and anti- tumor immune response, through non-telomeric TRF2. Therefore, we propose telomere length as a novel biomarker underlying patient-specific response to cancer immunotherapy.

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“… 3 In therapy-naïve cutaneous melanoma metastases, TILs score was also shown to be a potential predictive biomarker for response and survival outcomes to anti-PD-1-based immunotherapy, similarly confirming previous observations in other tumors, as in breast cancer 2 and providing still more evidence that quantity of immune-infiltrates matter. 4 , 5 …”

mentioning

confidence: 99%

Artificial intelligence biomarkers for digital oncology: a case study of tumor-infiltrating lymphocytes in melanoma

Salgado,

AbdulJabbar

2023

eBioMedicine

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Quantity of Immune Cells Predict Response to Immunotherapy in Cancer

Cited by 6 publications

References 9 publications

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

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

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

Artificial intelligence biomarkers for digital oncology: a case study of tumor-infiltrating lymphocytes in melanoma

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