General Information
- Project ID
- OEP003840
- Project Name
- Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway
- Description
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and bears dismal prognosis due to the lack of effective treatments. While immunotherapy has made great strides in other cancers, the outcomes of immune checkpoint inhibitors (ICIs) treatment in PDAC are disheartening. Here we demonstrate that tumor cell-intrinsic Setd2-knockout sensitizes PDAC tumors to ICIs immunotherapy in syngeneic murine models. Mechanistically, via an integrated multiomics analysis using ATAC-seq, ChIP-seq and RNA-seq, we reveal that SETD2 inactivation reduces NR2F1 transcription by impairing H3K36me3 deposition and chromatin accessibility. As a repressive transcription factor to STAT1, down-regulated NR2F1 activates IFNγ-STAT1 pathway to promote chemokine production, PD-L1 expression and enhance MHC-I antigen presentation. Upregulated chemokines reprogram intratumoral immune cells and inflame the tumor microenvironment with high-infiltrated T cells through bulk and single-cell RNA-seq analysis. Enhanced MHC-I antigen presentation profoundly promotes the cytotoxity of CD8+ T cells. With a blockade to the highly expressed PD-L1, the inflamed intratumoral immune cells significantly inhibits the tumor growth in PDAC. The SETD2-NR2F1-STAT1 regulatory axis is conserved in human and murine PDAC, suggesting a sign of clinical benefit for patients harboring SETD2 deficiency. Together, our findings provide novel insights into the regulation of tumor cell-intrinsic SETD2 inactivation to immune microenvironment, and reveal a potential biomarker for ICIs treatment in refractory PDAC.
Project information
- Experiments
- 5
- Samples
- 7
Sample ID Sample Name Sample Subject Type Organism Tissue Create Date OES293723 KC-ctrl Cell line Mus musculus cell line 2023-01-13 OES293724 KC-sgSetd2 Cell line Mus musculus cell line 2023-01-13 OES293725 YAPC-ctrl Cell line Homo sapiens cell line 2023-01-13 OES293726 YAPC-sgSETD2 Cell line Homo sapiens cell line 2023-01-13 OES293727 KC-KO Cell line Mus musculus cell line 2023-01-13 OES293728 KC-WT Cell line Mus musculus cell line 2023-01-13 OES293729 Normal Animalia Mus musculus pancreas 2023-01-13 - Runs
-
31
Run ID Run Name Experiment Sample Data Num Create Date OER377397 KC-sgSetd2-PD-L1_L001_scRNA-seq OEX021187 OES293724 2 2023-01-14 OER377398 KC-sgSetd2-PD-L1_L002_scRNA-seq OEX021187 OES293724 2 2023-01-14 OER377399 KC-sgSetd2-PBS_L002_scRNA-seq OEX021187 OES293724 2 2023-01-14 OER377400 KC-sgSetd2-PBS_L001_scRNA-seq OEX021187 OES293724 2 2023-01-14 OER377401 KC-ctrl-PD-L1_L002_scRNA-seq OEX021187 OES293723 2 2023-01-14 OER377402 KC-ctrl-PD-L1_L001_scRNA-seq OEX021187 OES293723 2 2023-01-14 OER377403 KC-ctrl-PBS-PBS_L002_scRNA-seq OEX021187 OES293723 2 2023-01-14 OER377404 KC-ctrl-PBS-PBS_L001_scRNA-seq OEX021187 OES293723 2 2023-01-14 OER377405 YAPC-sgSETD2_RNA-seq OEX021188 OES293726 1 2023-01-14 OER377406 YAPC-ctrl_RNA-seq OEX021188 OES293725 1 2023-01-14 OER377407 KC-WT#3_RNA-seq OEX021188 OES293728 1 2023-01-14 OER377408 KC-WT#2_RNA-seq OEX021188 OES293728 1 2023-01-14 OER377409 KC-WT#1_RNA-seq OEX021188 OES293728 1 2023-01-14 OER377410 KC-sgSetd2_RNA-seq OEX021188 OES293724 1 2023-01-14 OER377411 KC-KO#3_RNA-seq OEX021188 OES293727 1 2023-01-14 OER377412 KC-KO#2_RNA-seq OEX021188 OES293727 1 2023-01-14 OER377413 KC-KO#1_RNA-seq OEX021188 OES293727 1 2023-01-14 OER377414 KC-ctrl_RNA-seq OEX021188 OES293724 1 2023-01-14 OER377392 Normal_WES OEX021189 OES293729 2 2023-01-14 OER377393 KC_sgSetd2_D66_WES OEX021189 OES293724 2 2023-01-14 OER377394 KC_sgSetd2_D5_WES OEX021189 OES293724 2 2023-01-14 OER377395 KC_ctrl_D66_WES OEX021189 OES293723 2 2023-01-14 OER377396 KC_ctrl_D5_WES OEX021189 OES293723 2 2023-01-14 OER377415 KC-WT_Input_ChIP-seq OEX021190 OES293728 2 2023-01-14 OER377416 KC-WT_ChIP-seq OEX021190 OES293728 2 2023-01-14 OER377417 KC-KO_Input_ChIP-seq OEX021190 OES293727 2 2023-01-14 OER377418 KC-KO_ChIP-seq OEX021190 OES293727 2 2023-01-14 OER377419 KC-sgSetd2#2_ATAC-seq OEX021191 OES293724 2 2023-01-14 OER377420 KC-sgSetd2#1_ATAC-seq OEX021191 OES293724 2 2023-01-14 OER377421 KC-ctrl#2_ATAC-seq OEX021191 OES293723 2 2023-01-14 OER377422 KC-ctrl#1_ATAC-seq OEX021191 OES293723 2 2023-01-14
Author Information
- Create Date
- 2023-01-11
- Last Modified
- 2023-10-31
- Submission
- Yuexiang Wang
- Shanghai Institute of Nutrition and Health