Telomere-Dependent Interleukin-1 Receptor Activation Promotes Immune Suppression in Triple-Negative-Breast Cancer

Abstract

AbstractThe 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.