B cell-derived IL35 drives STAT3-Dependent CD8+ T-cell Exclusion in Pancreatic Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA603804 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10987245_1.fastq.gz | Fastqsanger.gz | |||
| SRR10987245_2.fastq.gz | Fastqsanger.gz | |||
| SRR10987246_1.fastq.gz | Fastqsanger.gz | |||
| SRR10987246_2.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.
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Project description:This study is designed to understand the role of immunosuppressive regulatory B cells (Breg) in pancreatic cancer. Breg and conventional B cells (Bcon) from patients are compared by RNA sequencing analysis.
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Project description:In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remain not well understood. Here, we found STAT3 signaling plays essential roles in promoting intra-tumor Texterm cell development, by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while suppresses those expressed by progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits developing more effective immunotherapies against tumor.
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Project description:In cancer, persistent antigens drive CD8+ T cell differentiation into exhausted progenitor (Texprog) and terminally exhausted (Texterm) cells. However, how the extrinsic and intrinsic regulatory mechanisms cooperate during this process still remain not well understood. Here, we found STAT3 signaling plays essential roles in promoting intra-tumor Texterm cell development, by enhancing their effector functions and survival, which results in better tumor control. In tumor microenvironments, STAT3 is predominantly activated by IL-10 and IL-21, but not IL-6. Besides, STAT3 also plays critical roles in the development and function of terminally differentiated effector CD8+ T cells in acute infection. Mechanistically, STAT3 transcriptionally promotes the expression of effector function-related genes, while suppresses those expressed by progenitor Tex subset. Moreover, STAT3 functions in collaboration with BATF and IRF4 to mediate chromatin activation at effector gene loci. Thus, we have elucidated the roles of STAT3 signaling in terminally differentiated CD8+ T cell development, especially in cancer, which benefits developing more effective immunotherapies against tumor.
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