scholarly journals LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Katherine J. Carpenter ◽  
Aurore-Cecile Valfort ◽  
Nick Steinauer ◽  
Arindam Chatterjee ◽  
Suomia Abuirqeba ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
Tumor Immune Evasion ◽  
Tumor Destruction ◽  
Immune Mediated

AbstractTriple-negative breast cancer (TNBC) is a highly aggressive subtype that is untreatable with hormonal or HER2-targeted therapies and is also typically unresponsive to checkpoint-blockade immunotherapy. Within the tumor microenvironment dysregulated immune cell metabolism has emerged as a key mechanism of tumor immune-evasion. We have discovered that the Liver-X-Receptors (LXRα and LXRβ), nuclear receptors known to regulate lipid metabolism and tumor-immune interaction, are highly activated in TNBC tumor associated myeloid cells. We therefore theorized that inhibiting LXR would induce immune-mediated TNBC-tumor clearance. Here we show that pharmacological inhibition of LXR activity induces tumor destruction primarily through stimulation of CD8+ T-cell cytotoxic activity and mitochondrial metabolism. Our results imply that LXR inverse agonists may be a promising new class of TNBC immunotherapies.

Abstract A15: Mechanisms of CD8+ T cell immunosuppression in triple negative breast cancer

2016 ◽  
Author(s):  
Tina Gruosso ◽  
Mathieu Gigoux ◽  
Nicholas Bertos ◽  
Sadiq Saleh ◽  
Atilla Omeroglu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cd8 T Cell

scholarly journals CD8 T Cell Score as a Prognostic Biomarker for Triple Negative Breast Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6968 ◽  
Author(s):  
Masanori Oshi ◽  
Mariko Asaoka ◽  
Yoshihisa Tokumaru ◽  
Li Yan ◽  
Ryusei Matsuyama ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Cytolytic Activity ◽  
Breast Cancer Patients

CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC and various GEO cohorts. The CD8 score correlated strongly with expression of CD8 genes. The score was highest for triple-negative breast cancer (TNBC), and a high score was associated with high tumor immune cytolytic activity and better survival in TNBC but not other breast cancer subtypes. In TNBC, tumors with a high CD8 score had enriched expression of interferon (IFN)-α and IFN-γ response and allograft rejection gene sets, and greater infiltration of anti-cancerous immune cells. The score strongly correlated with CD4 memory T cells in TNBC, and tumors with both a high CD8 score and high CD4 memory T cell abundance had significantly better survival. Finally, a high CD8 score was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, a high CD8 T cell score is associated with better survival in TNBC, particularly when tumor CD4 memory T cells were elevated. Our findings also suggest a possible use of the score as a predictive biomarker for response to immune checkpoint therapy.

scholarly journals PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer

2019 ◽  
Vol 9 (6) ◽  
pp. 722-737 ◽  
Author(s):  
Constantia Pantelidou ◽  
Olmo Sonzogni ◽  
Mateus De Oliveria Taveira ◽  
Anita K. Mehta ◽  
Aditi Kothari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Cd8 T Cell ◽  
Cell Recruitment ◽  
Pathway Activation ◽  
Sting Pathway

scholarly journals NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Ge Qin ◽  
Xin Wang ◽  
Shubiao Ye ◽  
Yizhuo Li ◽  
Miao Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cell Activity

scholarly journals Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T cell evasion in triple negative breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dora Hammerl ◽  
John W. M. Martens ◽  
Mieke Timmermans ◽  
Marcel Smid ◽  
Anita M. Trapman-Jansen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Triple Negative ◽  
Immune Cell ◽  
Phase Ii Trial ◽  
Checkpoint Inhibitors ◽  
High Density ◽  
Enhanced Expression

AbstractOnly a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyze 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes and pathways of T cell evasion. Excluded, ignored and inflamed phenotypes can be captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which is associated with resistance to anti-PD1, demonstrates deposits of collagen-10, enhanced glycolysis, and activation of TGFβ/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, shows either high density of CD163+ myeloid cells or activation of WNT/PPARγ pathways; whereas the inflamed phenotype, which is associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T cell co-inhibitory receptors.

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