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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE138483 | GEO | 2023/12/31

REPOSITORIES: GEO

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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [Essen]

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.

2023-12-31 | GSE138481 | GEO

MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [Verona]

2023-12-31 | GSE138477 | GEO

MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [RNA-Seq]

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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer

Project description:MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer

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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [Essen]

Project description:MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [Essen]

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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [Verona]

Project description:MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [Verona]

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MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [RNA-Seq]

Project description:MAP Kinase inhibition depletes tumor-infiltrating macrophages in mouse pancreatic cancer [RNA-Seq]

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Targeting tumor-infiltrating macrophages to combat cancer.

Project description:Tumor-associated macrophages are one of the major constituents of tumor stroma in many solid tumors and there is compelling preclinical and clinical evidence that macrophages promote cancer initiation and malignant progression. Therefore, these cells represent potential targets for therapeutic benefit. In this review, we will summarize macrophage phenotypic heterogeneity, the current understanding of how tumors take advantage of macrophage plasticity to generate immunosuppression, and how manipulation of specific macrophage populations can be used for therapeutic purposes through translational approaches.

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Targeting Proliferating Tumor-Infiltrating Macrophages Facilitates Spatial Redistribution of CD8+ T Cells in Pancreatic Cancer.

Project description:Tumor-associated macrophages (TAMs) play crucial roles in cancer progression, but the contributions and regulation of different macrophage subpopulations remain unclear. Here, we report a high level of TAM infiltration in human and mouse pancreatic ductal adenocarcinoma (PDAC) models and that the targeting of proliferating F4/80+ macrophages facilitated cytotoxic CD8+ T-cell-dependent antitumor immune responses. A well-defined KPC-derived PDAC cell line and the murine Panc02 PDAC cell line were used. Treatment of PDAC-bearing mice with clodronate liposomes, an agent that chemically depletes macrophages, did not impact macrophage subpopulations in the local tumor microenvironment (TME). However, further investigation using both BrdU and Ki67 to evaluate proliferating cells showed that clodronate liposomes treatment reduced proliferating macrophages in the KPC and Panc02 models. We further evaluated the distance between CD8+ T cells and PanCK+ tumor cells, and clodronate liposomes treatment significantly increased the number of CD8+ T cells in close proximity (<30 µm) to PanCK+ PDAC cells, with increased numbers of tumor-infiltrating IFN-γ+CD8+ T cells. This study suggests that targeting proliferating tumor-infiltrating macrophages may increase CD8+ cytotoxic lymphocyte (CTL) infiltration and facilitate the spatial redistribution of CD8+ T cells in tumors, contributing to the antitumor effect.

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