Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

ePoster Display

1184P - Necroptosis establishes an inflammatory tumor immune microenvironment acting as tumor suppressor in lung adenocarcinoma

Date

16 Sep 2021

Session

ePoster Display

Topics

Tumour Immunology;  Cancer Biology;  Translational Research

Tumour Site

Non-Small Cell Lung Cancer

Presenters

Fabian Allmendinger

Citation

Annals of Oncology (2021) 32 (suppl_5): S939-S948. 10.1016/annonc/annonc728

Authors

F. Allmendinger1, D. Agrawal1, M. Dietzen2, S. Vosberg3, E. Munkhbaatar1, N. McGranahan2, P.J. Jost3

Author affiliations

  • 1 Department Of Internal Medicine Iii, TUM - Technical University of Munich, 80333 - Munich/DE
  • 2 Cancer Research Uk Lung Cancer Center Of Excellence, UCL Cancer Institute/Paul O'Gorman Building, WC1E 6JD - London/GB
  • 3 Division Of Clinical Oncology, Department Of Medicine, Medical University of Graz, A-8036 - Graz/AT
More

Abstract 1184P

Background

Receptor-Interacting Serin/Threonin-Protein Kinase 3 (RIPK3) mediates necroptosis, a programmed form of cell death, which elicits the release of intracellular contents (DAMPs) and cytokines. These substances attract and activate anti-tumoral immune cells, rendering necroptosis highly immunogenic. In lung adenocarcinomas (LUAD), RIPK3 is a tumor suppressive aberrational target, which has been shown to induce immune suppression in the tumor microenvironment.

Methods

To investigate RIPK3 in human LUAD, we took advantage of The Cancer Genome Atlas program (TCGA) and primary samples. We further studied RIPK3 in a LUAD mouse model, carrying Kras G12D oncogene as well as Cas9 (both under a floxed stop codon) and floxed p53 tumor suppressor. Tumor induction was obtained through Cre recombination, which induced Cas9 and Kras G12D activation as well as p53 deletion. Together with Cre we delivered single guide RNA for Cas9 activity directed against Ripk3 (sgRipk3) or the negative control LacZ (sgLacZ).

Results

Expression of RIPK3 was decreased in human LUAD tumors compared to paired healthy tissue, both at mRNA and protein levels. Moreover, RIPK3 expression was further decreased in advanced stage tumors. Leveraging the Danaher scores, as an index of immune infiltration, we identified that high RIPK3 expression correlates with an overall enrichment of tumor infiltrating leukocytes, such as T-cells, B-cells, macrophages, and dendritic cells. In LUAD mice exposed to sgRipk3, the Cre-recombination did not show a full penetrance, therefore eliciting Ripk3 proficient and deficient lesions within the same animal. Interestingly, the tumor area of Ripk3 deficient lesions was significantly higher than Ripk3 proficient lesions. Analysis of the sgLacZ group revealed an heterogenous Ripk3 expression profile in tumors, where more advanced and bigger tumors showed weaker expression of Ripk3, suggesting that tumors actively evade Ripk3 expression.

Conclusions

Taken together our data clearly point to RIPK3 as a tumor suppressor in LUAD. This effect may be driven by the inhibition of necroptotic cell death, which in turn alters immune cell recruitment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Deutsche Forschungsgemeinschaft (DFG).

Disclosure

N. McGranahan: Financial Interests, Personal and Institutional, Stocks/Shares, received consultancy fees: Achilles Therapeutics. P.J. Jost: Financial Interests, Personal and Institutional, Advisory Role, Received Honoraria, Research Funding: AbbVie; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, travel/accomodation: Bayer; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, research funding, and/or travel/accommodation expenses: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, research funding, and/or travel/accommodation expenses: Novartis; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, travel/accommodation: Pfizer; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, travel/accommodation: Servier; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, research funding, and/or travel/accommodation expenses: Roche; Financial Interests, Personal and Institutional, Advisory Role, received honoraria, research funding, and/or travel/accommodation expenses: BMS/Celgene. All other authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.