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CD8+ T cells in the tumor immune microenvironment modulate resistance to endocrine therapy in hormone receptor-positive breast cancer

ABSTRACT: Enhanced immune infiltration in the tumor immune microenvironment (TIME) is associated with better survival outcomes in patients with triple negative and HER2+ breast cancers. In the hormone-dependent hormone receptor-positive (HR+) subtype, previous studies have identified a subgroup with enhanced immune infiltration. However, the biological significance and role of the TIME in modulating the response to anti-estrogen therapy in breast cancer are not well understood. Herein, using cyclic immunofluorescence and spatial transcriptomics (ST), we dissected the TIME in primary breast cancers that were sensitive or resistant to estrogen deprivation (ED) induced by the aromatase inhibitor letrozole. Stromal tumor-infiltrating lymphocytes (TILs) were increased in ED-resistant vs. ED-sensitive tumors. RNA-sequencing from on-treatment tumors showed differentially regulated pathways, including immune-related gene sets, such as upregulation of IFNɣ and IFNα signaling and allograft rejection. Spatial transcriptomics using GeoMx identified increased antigen processing and immune gene expression signatures in both cancer cells and neighboring immune cells in ED-resistant vs. ED-sensitive tumors. Using CIBERSORT, we uncovered a differential distribution of immune cell subtypes, with CD8+ T cells being enriched in ED-resistant tumors and Tregs in ED-sensitive tumors. The expression of chemokine genes involved in CD8+ T cell recruitment, CXCL9, CXCL10, and CXCL11, was upregulated in ED-resistant primary tumors before and after letrozole treatment. Additionally, CXCL11 levels were higher in media conditioned from HR+ breast cancer cells co-cultured with CD8+ T cells. Both recombinant CXCL11 and co-culture with CD8+ T cells stimulated the growth of HR+ breast cancer cells when deprived of estrogen, akin to the scenario of patients treated with letrozole. Taken together, these data suggest that CD8+T cells in the TIME modulate the response of HR+ breast cancer cells to therapeutic estrogen suppression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297605 | GEO | 2025/10/07

REPOSITORIES: GEO

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Project description:Enhanced immune infiltration in the tumor immune microenvironment (TIME) is associated with better survival outcomes in patients with triple negative and HER2+ breast cancers. In the hormone-dependent hormone receptor-positive (HR+) subtype, previous studies have identified a subgroup with enhanced immune infiltration. However, the biological significance and role of the TIME in modulating the response to anti-estrogen therapy in breast cancer are not well understood. Herein, using cyclic immunofluorescence and spatial transcriptomics (ST), we dissected the TIME in primary breast cancers that were sensitive or resistant to estrogen deprivation (ED) induced by the aromatase inhibitor letrozole. Stromal tumor-infiltrating lymphocytes (TILs) were increased in ED-resistant vs. ED-sensitive tumors. RNA-sequencing from on-treatment tumors showed differentially regulated pathways, including immune-related gene sets, such as upregulation of IFNɣ and IFNα signaling and allograft rejection. Spatial transcriptomics using GeoMx identified increased antigen processing and immune gene expression signatures in both cancer cells and neighboring immune cells in ED-resistant vs. ED-sensitive tumors. Using CIBERSORT, we uncovered a differential distribution of immune cell subtypes, with CD8+ T cells being enriched in ED-resistant tumors and Tregs in ED-sensitive tumors. The expression of chemokine genes involved in CD8+ T cell recruitment, CXCL9, CXCL10, and CXCL11, was upregulated in ED-resistant primary tumors before and after letrozole treatment. Additionally, CXCL11 levels were higher in media conditioned from HR+ breast cancer cells co-cultured with CD8+ T cells. Both recombinant CXCL11 and co-culture with CD8+ T cells stimulated the growth of HR+ breast cancer cells when deprived of estrogen, akin to the scenario of patients treated with letrozole. Taken together, these data suggest that CD8+T cells in the TIME modulate the response of HR+ breast cancer cells to therapeutic estrogen suppression.

Project description:Resistance to endocrine therapy agents has presented a clinical obstacle in the treatment of hormone-dependent breast cancer. Our laboratory has initiated a study of microRNA regulation of signaling pathways that may result in breast cancer progression on aromatase inhibitors (AI). Microarray analysis of microRNA expression identified 115 significantly regulated microRNAs, of which 49 microRNAs were believed to be hormone-responsive. Within the AI-resistant cells, microRNAs were differentially expressed between the steroidal and non-steroidal AI-resistant lines. Also, a group of microRNAs were inversely expressed in the AI-resistant lines versus LTEDaro and tamoxifen-resistant. We focused our work on hsa-miR-128a which was hormone-responsive and up-regulated in the letrozole-resistant cell lines. Human miR-128a was shown to negatively target TGFBRI protein expression by binding to the 3âUTR region of the gene. Loss of TGFBRI resulted in compromised sensitivity to the growth inhibitory effects of TGFB in the letrozole-resistant lines. Inhibition of endogenous miR-128a resulted in re-sensitization of the letrozole-resistant lines to TGFB growth inhibitory effects. This data suggests that the hormone-responsive miR-128a can modulate TGFB signaling and survival of the letrozole-resistant cell lines. To our knowledge, this is the first study to address the role of microRNA regulation as well as TGFB signaling in AI-resistant breast cancer cell lines. We believe that in addition to estrogen-modulation of gene expression, hormone-regulated microRNAs may provide an additional level of post-transcriptional regulation of signaling pathways critically involved in breast cancer progression and AI-resistance. To look at microRNA expression profiles of breast cancer cell lines derived from MCF-7 cells that are resistant to endocrine therapy agents. MCF-7 cells that overexpress aromatase (MCF-7aro) were cultured long-term in the presence of endocrine therapy agents until cells acquired resistance. Three different aromatase inhibitors (letrozole, anastrozole or exemestane) were used, as well as the ER antagonist tamoxifen, or the hormone-free long-term estrogen deprived cells (LTED). Three replicates of the control cells (MCF-7aro) and all resistant cells were used for microarray experiments. Total of 23 samples were analyzed by microarray.

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CD8+ T cells in the tumor immune microenvironment modulate resistance to endocrine therapy in hormone receptor-positive breast cancer

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