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Tumor infiltrating exhausted CD8+ T cells dictate divergent survival outcomes in pre- versus post-menopausal estrogen receptor-positive breast cancer

ABSTRACT: CD8+ tumor infiltrating lymphocytes (TILs) are associated with improved survival in triple negative breast cancer (TNBC), yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identify subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibit a distinct tumor microenvironment marked by amplified interferon-γ signaling related pathways and higher PD-L1 expression. Paradoxically, high levels of CD8+ TEX TILs associate with decreased overall survival ER+ BC patients, but not TNBC patients. Moreover, high tumor expression of a CD8+ TEX signature identifies dramatically reduced survival in pre-menopausal, but not post-menopausal, ER+ BC patients. Finally, we demonstrate the value of a tumor TEX signature score in identifying high-risk pre-menopausal ER+ BC patients amongst those with intermediate Oncotype Dx breast recurrence scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and estrogen receptor status in BC patient survival. This work identifies pre-menopausal ER+ BC patients with high levels of tumor infiltrating CD8+ TEX as a high-risk subset that may benefit from immunotherapy strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190202 | GEO | 2022/02/23

REPOSITORIES: GEO

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Tumor infiltrating CD8+ Tex cells dictate divergent survival outcomes in pre- vs post-menopausal ER+ breast cancer

Project description:Tumor infiltrating CD8+ Tex cells dictate divergent survival outcomes in pre- vs post-menopausal ER+ breast cancer

| PRJNA786200 | ENA

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy

Project description:Identifying signals that govern the differentiation of tumor-infiltrating CD8 + T cells (CD8 + TILs) towards exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues enhancing terminal CD8 + T cell exhaustion in tumors. We found enrichment of IFNIs-stimulated genes (ISGs) within exhausted CD8 + T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8 + TILs devoid of IFN-Is signaling developed less exhaustion features, provided better tumor control and showed greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-Is stimulation perturbed lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promoted lipid peroxidation, which potentiated metabolic and functional exhaustion of Tex cells. Thus, cell intrinsic IFN-Is signaling regulates the extent of CD8+ TIL exhaustion, and has important implications for immunotherapy.

2022-11-16 | GSE212699 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [ATAC-Seq]

2022-11-16 | GSE212698 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [RNA-Seq]

2022-11-16 | GSE212697 | GEO

Tumor infiltrating CD8+ Tex cells dictate divergent survival outcomes in pre- vs post-menopausal ER+ breast cancer

Project description:We identify subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibit a distinct tumor microenvironment marked by amplified interferon-γ signaling related pathways and higher PD-L1 expression.

2022-02-23 | GSE190169 | GEO

An unconventional integrin b3 and CD103 heterodimer improves the anti-tumor immunity of tissue-resident T cells

Project description:Current cancer immunotherapies promote recovery of CD103+ tissue-resident memory T cells (Trm) population of the tumor-infiltrating T lymphocytes (TILs). However, not all treated patients exhibit improved anti-tumor immunity and survival, likely due to the immunophenotypical diversity among the CD103+ Trm TILs. Utilising multifaceted proteomics approaches and patients’ clinical analyses, we discovered an unusual subset of CD8+ Trm TILs expressing non-canonical integrin β3 early during T cells activation. The integrin β3 surprisingly heterodimerises with CD103 on T cells, leading to unconventional granulysin-mediated cytotoxicity, elevated alternative bioenergy usage and efficient T cell migration, with minimal overall exhaustion. Importantly, early-stage non-small cell lung carcinoma (NSCLC) patients with enriched presence of integrin β3+CD103+ Trm TILs exhibited better clinical prognosis, with improved T cell immunophenotype, hence confirming the beneficial role of this unusual subset of Trm TILs. These unconventional anti-tumor T cell features provide new avenues and future opportunities for designing better translational immunotherapy strategies.

2024-02-14 | PXD031794 | Pride

Expression data from FACS-sorted CD8+BTLA+ vs CD8+BTLA- Human Tumor-infiltrating Lymphocytes in Metastatic Melanoma

Project description:Adoptive T-cell Therapy (ACT) involves using tumor-infiltrating lymphocytes (TIL) isolated from metastatic melanoma and expanding them ex vivo prior to infusion into lympho-depleted patients. This is one of the most promising approaches to treat metastatic melanoma, with the rates of clinical response between 48-50% based on studies done at NCI, M.D. Anderson Cancer Center (Houston, TX), and Sheba Medical Center (Tel Aviv, Israel). In the Phase II ACT Trial at M.D. Anderson Cancer Center , our group has uncovered an association between positive clinical response and the amount of CD8+ tumor-infiltrating lymphocytes expressing B and T Lymphocyte Attenuator (BTLA), a reported inhibitory receptor on T-cells. We used microarrays to detail the differences in the global programme of gene expression between CD8+BTLA+ vs CD8+BTLA- TILs in order to understand the molecular basis of the clinical association. TILs were isolated by enzymatically digest the melanoma tumor fragments obtained from Stage IIIc/IV melanoma patients at M.D. Anderson Cancer Center. The TILs were expanded with high-dose IL-2 for two weeks prior to sorting by FACS (fluoresecence-activated cell sorter) for CD8+BTLA+ and CD8+BTLA- susbets. RNA was extracted from each sorted subsets and hybridized on Affymetrix microarrays

2013-01-03 | E-GEOD-43260 | biostudies-arrayexpress

GR and ER co-activation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome

Project description:Analysis of MCF-7 cells treated for 4h with Ethanol, Estradiol (E2), Dexamethasone (Dex), or Estradiol + Dexamethasone (E2 + Dex) In estrogen receptor (ER)-negative breast cancer (BC), high tumor glucocorticoid receptor (GR) expression has been associated with a relatively poor outcome. In contrast, using a meta-analysis of several genomic datasets, here we find that tumor GR mRNA expression is associated with improved ER+ relapse-free survival (RFS) (independently of progesterone receptor (PR) expression). To understand the mechanism by which GR expression is associated with a better ER+ BC outcome, the global effect of GR-mediated transcriptional activation in ER+ BC cells was studied. Analysis of GR chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in ER+/GR+ MCF-7 cells revealed that upon co-activation of GR and ER, GR chromatin association became enriched at proximal promoter regions. Furthermore, following ER activation, increased association of GR was observed at ER, FOXO, and AP1 response elements. In addition, it was determined that ER associated with GR response elements, suggesting that ER and GR interact in a complex. Co-activation of GR and ER resulted in increased expression (relative to ER activation alone) of transcripts that encode proteins promoting cellular differentiation (e.g. KDM4B, VDR) and inhibiting Wnt-signaling (IGFBP4). Finally, expression of these individual pro-differentiation genes was associated with significantly improved RFS in ER+ BC patients. Together, these data demonstrate that the co-expression and subsequent activity of tumor cell GR and ER contribute to the less aggressive natural history of early-stage BC by coordinating the altered expression of genes favoring differentiation. Four treatment samples (Vehicle V, Dex D, E2, or Dex+E2). Three biological replicate experiments per sample. Vehicle sample is Ethanol control.

2016-04-01 | E-GEOD-79761 | biostudies-arrayexpress

FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells

Project description:Background: OX40 (CD134) is a co-stimulatory molecule of the tumor necrosis factor receptor (TNFR) superfamily, that is currently investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in treatment of cancer patients has fallen short of the high expectation in earlier stage trials. Methods: Using lymphocytes from resected tumor, tumor-free tissue and PBMC of 4 hepatocellular and colorectal cancer patients, we performed RNA-Seq to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs). Results: The transcriptional landscape of CD4+ and CD8+ TILs shifted towards a pro-survival, inflammatory and chemotactic profile upon treatment with αOX40_v12.

2020-06-22 | GSE152904 | GEO

GR and ER co-activation alters the expression of differentiation genes and associates with improved ER+ breast cancer outcome

2016-04-01 | GSE79761 | GEO

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