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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190169 | GEO | 2022/02/23

REPOSITORIES: GEO

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

Project description: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.

2022-02-23 | GSE190202 | GEO

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

Decitabine-induced T cell remodeling facilitates a high antitumor response to PD-1 blockade therapy by promoting the expansion and effector function of CD8+ progenitor exhausted T cells

Project description:CD8+ exhausted T (Tex) cells are heterogeneous with distinct transcriptional and epigenetic landscapes. PD-1 inhibitors reinvigorate progenitor Tex cells, which subsequently differentiate into irresponsive terminal Tex cells and impair the longlasting antitumor response of PD-1 blockade therapy. How to maintain durable proliferative capacity of progenitor Tex cells is important but remains largely unknown. Here, we showed that low-dose DNA demethylating agent decitabine-pretreated CD8+ progenitor Tex cells had enhanced cytolytic activity against tumors after anti-PD-1 treatment in vitro and could not reactivate the terminal Tex cells. Decitabine-plus-anti-PD-1 treatment promoted the activation and expansion of endogenous tumor-infiltrated CD8+ progenitor Tex cells and efficiently suppressed tumor growth in multiple mice tumor models. The single-cell RNA-sequencing, TCR-sequencing and ATAC-sequencing demonstrated that decitabine-plus-anti-PD-1 combination altered the transcriptional and epigenetic status of CD8+ Tex cells and markedly elevated the clonally expansion and effector function of progenitor Tex cells as compared with anti-PD-1 monotherapy, presenting increased expression of genes associated with T cell activation, proliferation, cytolytic activity, memory and mitochondrial metabolism. Strikingly, decitabine-plus-anti-PD-1 combination sustained the expression and activity of AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Suppressing JNK/AP-1 signaling in CD8+ T cells blunted decitabine-plus-anti-PD-1-induced activation of CD8+ T cells. Together, our findings show that the epigenetic therapy remodels CD8+ progenitor Tex subset, improves responsiveness to anti-PD-1 therapy and suppresses CD8+ T cell terminal differentiation.

2022-07-28 | GSE209965 | GEO

Profiling of lung tumor-infiltrating CD8 T cells according to their expression status of CD39

Project description:Human tumors are infiltrated by various immune cells, including CD8 T cells. CD8 T cells express unique receptors that can recognize peptides at the host’s cells, including tumor cells. After probing the antigen specificity of ex-vivo tumor-infiltrating CD8 T cells from human tumors, we hypothesized that expression of CD39 was correlated with tumor-specificity. The present experiment aims at better characterizing ex-vivo CD39+ vs CD39- CD8 T cells.

2018-05-17 | GSE113588 | GEO

Profiling of colorectal tumor-infiltrating CD8 T cells according to their expression status of CD39

2018-05-17 | GSE113585 | GEO

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

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

| PRJNA786331 | ENA

The immunopeptidome landscape associated with T cell infiltration, inflammation and immune-editing in lung cancer

Project description:One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. While patients with CD3+CD8+ T cell inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown if the repertoire of HLA bound peptides presented in highly inflamed and non-inflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent non-malignant lung tissues from eight lung cancer patients and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics and explored the heterogeneous expression and presentation of tumor (neo)antigens. Here we associated diverse immune cell populations with the immunopeptidome in CD3+CD8+ T cell excluded, infiltrated, highly- and lowly-inflamed tumors. We found evidence for lower immune-editing and higher presentation efficiency of tumor-associated antigens in lowly-inflamed and CD3+CD8+ T cell excluded tumors. This could have implications for the choice of combination therapies tailored to the patient’s mutanome and microenvironment.

2023-03-21 | PXD034772 | Pride

Divergent clonal differentiation trajectories of T cell exhaustion (scRNA-seq)

Project description:T cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (Tex) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. However, whether all antigen-specific T cell clones follow the same molecular and cellular Tex differentiation trajectory remains unclear. Here, we generate a single-cell multi-omic atlas of T cell exhaustion that redefines the phenotypic diversity and molecular regulation of Tex phenotypes. Longitudinal analysis during chronic viral infection identifies an early effector phenotype that is epigenetically primed for Tex differentiation and two late-stage Tex cell states with either a terminal exhaustion or a killer cell lectin-like receptor (KLR)-expressing cytotoxic gene signature. We define clonal trajectories of antigen-specific T cells using paired single-cell RNA and T cell receptor sequencing and reveal distinct differentiation trajectories resulting in terminal Tex-biased, KLR Tex-biased, or divergent clones that differentiate into both phenotypes. Comparison of Tex phenotypes among shared T cell clones that traffic to multiple organs reveals that clonal differentiation trajectories are maintained across tissues. Finally, we show that differences in clonal differentiation trajectory are driven by TCR signaling avidity, whereby high-avidity T cell clones preferentially adopt a terminal Tex fate, while low-avidity clones adopt an effector-like KLR Tex fate. These findings reveal clonal heterogeneity in the T cell response to chronic antigen and genomic programs that underlie Tex fates and persistence.

2022-07-25 | GSE188666 | GEO

Single-Cell Sequencing Reveals the Overall Changes in Tumor Microenvironment Mediated by CD39i

Project description:Here we identified the ecto-enzyme, CD39 (encoded by ENTPD1), as a potential therapeutic target for BC via single-cell transcriptome analysis of BC and para-cancer tissues. In a subcutaneous model, inhibition of CD39 (CD39i) is able to limit the growth of BC and improve overall survival of tumor-bearing mice. Via single-cell sequencing of tumor infiltrated immune cells, we found that CD39i with POM-1 increased the intratumor NK cells, conventional type 1 dendritic cells (cDC1) and CD8+ T cells, along with decreased Treg abundance. The anti-tumor effect and reprogram of tumor microenvironment are blockade in a cDC1-deficient Batf3−/− model.

2022-09-06 | GSE189127 | GEO

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

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