MAP Kinase inhibition reshapes tumor microenvironment of mouse pancreatic cancer by depleting anti-inflammatory macrophages
Sabrina L. D’Agosto,
Gael D. Temgue Tane,
Francesco De Sanctis,
Rita T. Lawlor,
Phyllis F. Cheung,
Jens T. Siveke,
Posted 08 Sep 2019
bioRxiv DOI: 10.1101/759779
Posted 08 Sep 2019
The RAF/MEK/ERK (MAP Kinase) pathway is the index oncogenic signaling towards which many compounds have been developed and tested for the treatment of KRAS-driven cancers, including pancreatic ductal adenocarcinoma (PDA). Here, we explored the immunological changes induced by targeted MEK1/2 inhibition (MEKi) using trametinib in preclinical mouse models of PDA. We evaluated the dynamic changes in the immune contexture of mouse PDA upon MEKi using a multidimensional approach (mRNA analyses, flow cytometry, and immunophenotyping). Effect of MEKi on the viability and metabolism of macrophages was investigated in vitro. We showed that transcriptional signatures of MAP Kinase activation are enriched in aggressive human PDA subtype (squamous/basal-like/quasimesenchymal), while short term MEKi treatment in mouse PDA induced subtype switching. Integrative mRNA expression and immunophenotypic analyses showed that MEKi reshapes the immune landscape of PDA by depleting rather than reprogramming macrophages, while augmenting infiltration by neutrophils. Depletion of macrophages is observed early in the course of in vivo treatment and is at least partially due to their higher sensitivity to MEKi. Tumor-associated macrophages were consistently reported to interfere with gemcitabine uptake by PDA cells. Here, our in vivo studies show a superior antitumor activity upon combination of MEKi and gemcitabine using a sequential rather than simultaneous dosing protocol. Our results show that MEK inhibition induces a dramatic remodeling of the tumor microenvironment of mouse PDA through depletion of macrophages, which substantially improves the antitumor activity of gemcitabine.
- Downloaded 283 times
- Download rankings, all-time:
- Site-wide: 52,786 out of 85,018
- In cancer biology: 1,686 out of 2,981
- Year to date:
- Site-wide: 35,401 out of 85,018
- Since beginning of last month:
- Site-wide: 41,359 out of 85,018
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!