Ontology highlight
ABSTRACT:
PROVIDER: PRJNA889326 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21857700.fastq.gz | Fastqsanger.gz | |||
| SRR21857701.fastq.gz | Fastqsanger.gz | |||
| SRR21857702.fastq.gz | Fastqsanger.gz | |||
| SRR21857703.fastq.gz | Fastqsanger.gz | |||
| SRR21857704.fastq.gz | Fastqsanger.gz |
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2022-12-14 | GSE218161 | GEO
Project description:The mechanisms by which parity and breastfeeding mediate protection against breast cancer, particularly triple-negative breast cancer (TNBC), remain unclear. CD8+ T cells with a tissue-resident-like phenotype (TRM) are present in TNBCs and are associated with better clinical outcomes. In preclinical models of TNBC, CD8+ TRM-like cells can protect against BC recurrences. These cells are also present in healthy, non-cancer-affected breast tissue. We hypothesized that post-lactational involution could facilitate increased CD8+ T cell recruitment locally to the breast, improving immune surveillance against BC. Consistent with this, we observed significantly higher quantities of immune cells and CD103+CD8+ T cells in healthy breast tissue collected from parous vs. nulliparous women. In preclinical murine models, we observed that after a period of lactation and involution, CD8+ TRM-like cells increase in quantity the mammary gland. Using syngeneic models of TNBC, we show that these higher quantities of local CD8+ T cells in the mammary gland are associated with significantly decreased tumor growth, with higher intratumoral T cell content. We further find that parous women vs. nulliparous women who develop primary TNBC have significantly higher T cell infiltration in their tumors. Our data provide evidence that lactation and post-lactational involution result in quantitative and qualitative differences in local resident CD8+ T cells that can restrain mammary tumor outgrowth.
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Project description:Analyses of healthy tissue reveal signatures that identify resident memory CD8+ T cells (TRM), which survey tissues without recirculating. The density of TRM-phenotype cells within solid tumors correlates favorably with prognosis, suggesting that intratumoral residents control cancer. However, residence has not been directly tested and intratumoral TRM-phenotype cells could instead reflect aspects of the microenvironment that correlate with prognosis. Using a breast cancer model, we found that conventional TRM markers do not inform the tumor residence of either bystander or tumor-specific cells, which exhibit further distinct phenotypes in the tumor microenvironment and healthy mammary tissue. Rather, tumor-specific, stem-progenitor CD8+ T cells migrate to tumors and become resident while acquiring select markers of exhaustion. These data indicate that tonic antigen stimulation and the tumor environment drive distinct programs of residence compared to healthy tissues and that tumor immunity is sustained by continued migration of tumor-specific stem cells.
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Project description:Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide and available therapies, including immunotherapies, are ineffective for many patients. HCC is characterized by intratumoral hypoxia, and increased expression of hypoxia-inducible factor (HIF) 1a in the diagnostic biopsy is associated with patient mortality. Here we report the development of 32-134D, a low-molecular-weight compound that effectively inhibits gene expression mediated by HIF-1 and HIF-2 in HCC cells, and blocks human and mouse HCC tumor growth as monotherapy. In immunocompetent mice bearing Hepa1-6 HCC tumors, addition of 32-134D to anti-PD1 therapy increased the rate of tumor eradication from 25% to 67%. Treated mice showed no changes in appearance, behavior, body weight, hemoglobin or hematocrit. 32-134D altered the expression of a large battery of genes encoding proteins that mediate angiogenesis, glycolytic metabolism, and responses to innate and adaptive immunity. This altered gene expression led to significant changes in the tumor immune microenvironment, including a decreased percentage of tumor-associated macrophages and myeloid-derived suppressor cells, which mediate immune evasion, and an increased percentage of CD8+ T cells and natural killer cells, which mediate anti-tumor immunity. Taken together, these preclinical findings suggest that combining 32-134D with immune checkpoint blockade may represent a breakthrough therapy for HCC.
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Project description:Breast cancer is the most common cancer among women. However, the use of immune checkpoint inhibitors, that have revolutionized treatment of multiple cancers, unfortunately remain largely ineffective in most breast cancer patients. Here, we report the most comprehensive glycoproteome map in breast tumor cells, pointing to a key role of sialic acid modifications in mammary cancer. Genetic and pharmacologic inhibition of sialylation repolarizes the tumor microenvironment, leading to a reduction in myeloid-derived suppressor cells and a significant increase in Tcf7+ memory and CD8+ effector T cells. Mechanistically, sialylation controls cell surface expression of MHC class I and PD-1-ligand on the tumor cells. Functionally, in vivo interference with sialylation on breast cancer cells licenses CD8+ T cells to effectively kill the tumors. In multiple immunotherapy-resistant breast tumor models, we also show that the abrogation of sialylation sensitizes to anti-PD-1 immune checkpoint therapy. We further demonstrate that hyper-sialylation occurs in over half of human breast cancers tested and correlates with poor T cell infiltration. Our results establish sialylation as a central immunoregulator in breast cancer, orchestrating multiple pathways of immune evasion. Targeting tumor sialylation licenses immunologically inert mammary tumors to be efficiently eliminated by anti-cancer immunity and sensitizes to immune checkpoint therapy.
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Project description:Microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) is characterized by a cold tumor microenvironment, marked by sparse CD8⁺ T cell infiltration and resistance to immune checkpoint inhibitors (ICIs). To uncover regulators that limit CD8⁺ T cell infiltration in MSS CRC, we conducted an in vivo CRISPR/Cas9 screen targeting genes in CD8⁺ T cells using a CMT93 cell-derived tumor model. This screen identified Arid3b as a key negative regulator of CD8⁺ T cell tumor infiltration and antitumor activity. Genetic ablation of Arid3b in CD8⁺ T cells significantly enhanced their intratumoral accumulation and mediated robust tumor control. Mechanistically, Arid3b deficiency upregulated Runx3, promoting a tissue-resident memory phenotype and effector function. Notably, the benefits conferred by Arid3b knockout were abrogated by Runx3 deletion, indicating a Runx3-dependent mechanism. In summary, targeting ARID3B could offer a promising strategy to reshape the tumor microenvironment and sensitize MSS CRC to immunotherapy.
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Project description:Microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer (CRC) is characterized by a cold tumor microenvironment, marked by sparse CD8⁺ T cell infiltration and resistance to immune checkpoint inhibitors (ICIs). To uncover regulators that limit CD8⁺ T cell infiltration in MSS CRC, we conducted an in vivo CRISPR/Cas9 screen targeting genes in CD8⁺ T cells using a CMT93 cell-derived tumor model. This screen identified Arid3b as a key negative regulator of CD8⁺ T cell tumor infiltration and antitumor activity. Genetic ablation of Arid3b in CD8⁺ T cells significantly enhanced their intratumoral accumulation and mediated robust tumor control. Mechanistically, Arid3b deficiency upregulated Runx3, promoting a tissue-resident memory phenotype and effector function. Notably, the benefits conferred by Arid3b knockout were abrogated by Runx3 deletion, indicating a Runx3-dependent mechanism. In summary, targeting ARID3B could offer a promising strategy to reshape the tumor microenvironment and sensitize MSS CRC to immunotherapy.
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T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
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