Transcriptomic analysis of tumor infiltrating CD8+ T cells during PDAC progression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE147465 | GEO | 2020/05/27
REPOSITORIES: GEO
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Project description:Transcriptomic analysis of tumor infiltrating CD8+ T cells during PDAC progression
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Project description:The MAP Kinase pathway is the index oncogenic signaling towards which many compounds have been developed for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). How targeted MEK1/2 inhibition (MEKi) alters the tumor-microenvironment (TME) of PDA is poorly understood. Here, we showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype, while short term MEKi treatment in mouse PDA induced subtype switching. Moreover, MEKi induced depletion of tumor-infiltrating macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early during in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Since tumor-associated macrophages are consistently reported to interfere with gemcitabine uptake by PDA cells, we tested a sequential combination of MEKi and gemcitabine, which showed superior antitumor activity in vivo. These findings suggest that MEKi-induced TME remodeling might be exploited to increase therapeutic responses in PDA.
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Project description:The MAP Kinase pathway is the index oncogenic signaling towards which many compounds have been developed for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). How targeted MEK1/2 inhibition (MEKi) alters the tumor-microenvironment (TME) of PDA is poorly understood. Here, we showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype, while short term MEKi treatment in mouse PDA induced subtype switching. Moreover, MEKi induced depletion of tumor-infiltrating macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early during in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Since tumor-associated macrophages are consistently reported to interfere with gemcitabine uptake by PDA cells, we tested a sequential combination of MEKi and gemcitabine, which showed superior antitumor activity in vivo. These findings suggest that MEKi-induced TME remodeling might be exploited to increase therapeutic responses in PDA.
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Project description:Inactivation of tumor infiltrating lymphocytes (TILs) is one of the limiting factors of anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironment. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further reveals that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs during anti-tumor immunity, and that Tet2 inactivation could benefit anti-tumor immunity and suppress tumor growth.
2021-04-20 | GSE152496 | GEO
Project description:The MAP Kinase pathway is the index oncogenic signaling towards which many compounds have been developed for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). How targeted MEK1/2 inhibition (MEKi) alters the tumor-microenvironment (TME) of PDA is poorly understood. Here, we showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype, while short term MEKi treatment in mouse PDA induced subtype switching. Moreover, MEKi induced depletion of tumor-infiltrating macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early during in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Since tumor-associated macrophages are consistently reported to interfere with gemcitabine uptake by PDA cells, we tested a sequential combination of MEKi and gemcitabine, which showed superior antitumor activity in vivo. These findings suggest that MEKi-induced TME remodeling might be exploited to increase therapeutic responses in PDA.
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Project description:Immunotherapy approaches have been ineffective in pancreatic ductal adenocarcinoma (PDA), pointing to the need for additional avenues to target in the pancreatic cancer microenvironment. We previously discovered that tumor educated bone marrow derived macrophages express high levels of C-C Motif Chemokine Receptor 1 (CCR1). By single-cell RNA sequencing, we found CCR1 to be expressed predominantly by tumor associated macrophages (TAMs) and granulocytes in both human and mouse PDA. Thus, we sought to investigate the functional role of CCR1 in pancreatic cancer. Using KC; Ccr1-/- mice (Ptf1a-Cre; LSL-KrasG12D; Ccr1-/-), we determined that CCR1 is dispensable during pancreatic cancer initiation, although we observed increased CD8 T cell infiltration in KC; Ccr1-/- pancreata. Using syngeneic orthotopic PDA mouse models we discovered that CCR1 ablation in Ccr1-/- mice or pharmaceutical inhibition of CCR1 both resulted in reduced tumor growth. Further, CCR1 ablation prolonged the overall survival of KPC mice. Through mass cytometry (CyTOF) and co-immunofluorescence staining we showed CCR1 ablation elevated CD8 T cell cytotoxic activity in the orthotopic PDA model. Mechanistically we found TAMs lacking CCR1 expressed less Arginase 1 and CD206 -both immunosuppressive markers of macrophages- compared to wild type TAMs. Further, targeting both CCR1 and Arginase 1 synergized with immune checkpoint blockade anti-PD-L1 to enhance antitumor efficacy in orthotopic model of PDA. Together, our data is consistent with the notion that tumor associated macrophages lacking CCR1 expression are less immunosuppressive, consequently allowing increased CD8 T cell mediated anti-tumor immunity. Targeting CCR1 in combination with immune checkpoint blockade improves antitumor efficacy in pancreatic cancer.
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Project description:Here we systematically dissected PDA intrinsic mechanisms of immune evasion by in vitro and in vivo CRISPR screening. Beyond the conserved set of genes regulating anti-cancer immunity we identified Rnf31 and Vps4b as essential factors required for escaping CD8+ T cell-killing. While the absence of Rnf31 induced sensitivity to T cell killing through TNF-mediated apoptosis in murine cancer cells and human PDA organoids, loss of Vps4b abrogated functional autophagy, resulting in accumulation of CD8+ T cell-derived granzyme B and subsequent tumor cell lysis.
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Project description:Identifying tumor antigen-specific T cells from cancer patients has been a goal of tumor immunologists for several decades. Co-expression of CD103 and CD39 on CD8 TIL highly enriches for tumor-reactive T cells. CD39+CD103+ CD8 TIL have a distinct TCR repertoire compared to other CD8 TIL subsets and are clonally expanded within the tumor. They are highly enriched for tumor antigen recognition and efficiently killed autologous tumor cells. Patients with head and neck cancer whose CD8 TIL contained a higher frequency of CD39+CD103+ cells experienced a greater overall survival. This work describes a simple and effective method for detecting tumor-reactive CD8 TIL.
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Project description:Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q+ TAMs are regulated by an RNA N6-methyladenosine (m6A) program and modulate tumor-infiltrating CD8+ T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m6A methyltransferase Mettl14 drives CD8+ T cell differentiation along a dysfunctional trajectory, impairing CD8+ T cells to eliminate tumors. Mettl14-deficient C1q+ TAMs show a decreased m6A abundance on and a higher level of transcripts of Ebi3, a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8+ T cells and overcomes immunosuppressive impact in mice. We show that the METTL14-m6A levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an m6A methyltransferase in TAMs promotes CD8+ T cell dysfunction and tumor progression.
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Project description:Cancer cells utilize epigenetic alterations to acquire autonomous capabilities for tumor maintenance. Here, we show that pancreatic ductal adenocarcinoma (PDA) cells hijack super-enhancers (SEs) to activate the EVI1 gene with its tumor-intrinsic program. We demonstrate that SE is the vital cis-acting element to maintain aberrant EVI1 transcription in PDA cells. Related to disease progression and inferior survival outcomes in human PDA, functional experiments further show that EVI1 upregulation is the cause of aggressive tumor phenotypes. In particular, EVI1 mediates the resistance to anchorage-independent growth and enhanced motility in vitro, with efficient tumor propagation in vivo. EVI1-dependent activation of gene expression program attributes to these phenotypes, by which EVI1 drives the stepwise configuration of the active enhancer chromatin. In sum, our findings support the promise that EVI1 is a crucial driver of oncogenic transcription program in PDA cells. Further, we emphasize the instructive role of epigenetic aberrancy in establishing PDA tumorigenesis.
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