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

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

PROVIDER: PRJNA786200 | ENA |

REPOSITORIES: ENA

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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: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

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

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Project description:Tumors that contain tumor-infiltrating lymphocytes (TIL) with tissue-resident memory T cells (TRM) features are associated with better patient prognoses. While CD8+ T cells that target tumors often fail to restrain tumor growth due to progressive T cell exhaustion, pathogen-specific TRM survey tissues and sustain protective capacity for years. We identified protein homeostasis (proteostasis)-related E3 ubiquitin ligase genes shared by TRM and progenitor-exhausted TIL (TPEX), that are lost as TIL become terminally-exhausted (TEX). Sustained ligase expression led to increased TCF1+ T cell accumulation and improved anti-tumor function and less T cell exhaustion in chronic infection. Loss-of-function in cancer models impaired TIL accumulation and function and altered T cell differentiation in response to acute infection. Low-input mass spectrometry revealed abundant expression of protein degradation pathways by TEX, yet they accumulated unfolded proteins. Ligase overexpression rescued unfolded protein accumulation in TEX, demonstrating their functional contribution to proteostasis. Ligase overexpression in combination with immune checkpoint blockade led to improved survival from murine melanoma, demonstrating that the relationship between proteostasis and T cell differentiation opens up new avenues for cancer immunotherapy.

2026-04-21 | PXD070932 | Pride

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

2026-04-21 | PXD063865 | Pride

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function

Project description:Tumors that contain tumor-infiltrating lymphocytes (TIL) with tissue-resident memory T cells (TRM) features are associated with better patient prognoses. While CD8+ T cells that target tumors often fail to restrain tumor growth due to progressive T cell exhaustion, pathogen-specific TRM survey tissues and sustain protective capacity for years. We identified protein homeostasis (proteostasis)-related E3 ubiquitin ligase genes shared by TRM and progenitor-exhausted TIL (TPEX), that are lost as TIL become terminally-exhausted (TEX). Sustained ligase expression led to increased TCF1+ T cell accumulation and improved anti-tumor function and less T cell exhaustion in chronic infection. Loss-of-function alleles in T cells challenged with cancer models impaired TIL accumulation and function and altered T cell differentiation in response to acute infection. Mass spectrometry revealed abundant expression of protein degradation pathways by TEX, yet they accumulated unfolded proteins. Ligase overexpression rescued unfolded protein accumulation in TEX, demonstrating their functional contribution to proteostasis. Ligase overexpression in combination with immune checkpoint blockade led to improved survival from murine melanoma, demonstrating that the relationship between proteostasis and T cell differentiation opens up new avenues for cancer immunotherapy.

2026-04-30 | PXD067417 | Pride

Fluoribacter dumoffii Tex-KL

Project description:Fluoribacter dumoffii Tex-KL Genome sequencing and assembly

| PRJNA73347 | ENA

Daphnia pulex strain:TEX-9

Project description:Daphnia pulex strain:TEX-9 Genome sequencing

| PRJNA212292 | ENA

Daphnia pulex strain:TEX-21

Project description:Daphnia pulex strain:TEX-21 Genome sequencing

| PRJNA212296 | ENA

Control vs. Menopausal kidney cortex

Project description:Gene expression in kidney cortex of control mice and menopausal mice 8 weeks after mice entered menopause. Menopause was induced by injection of 4-vinylcyclohexene diepoxide.

2010-09-14 | GSE20703 | GEO

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