Dissecting Cross-Regulatory Interplays in Tumor-Associated Macrophages

Project Information

X-TAM

Grant agreement ID: 759532

DOI

10.3030/759532

Project closed

EC signature date 24 October 2017

Start date 1 March 2018

End date 31 August 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 498 125,00

EU contribution

€ 1 498 125,00

Coordinated by

OSPEDALE SAN RAFFAELE SRL
Italy

Periodic Reporting for period 4 - X-TAM (Dissecting Cross-Regulatory Interplays in Tumor-Associated Macrophages)

Reporting period: 2022-09-01 to 2023-08-31

Summary of the context and overall objectives of the project

Pancreatic cancer is one of the most aggressive forms of tumors, for which limited therapeutic options are available. The characterization of pathogenetic events in pancreatic cancer progression and the identification of novel therapeutic targets remain fundamental objectives in oncology. In this context, there is evidence that pancreatic cancer can subdue the host immune system by reprogramming the activity of a type of immune cells called macrophages. This project aimed at determining how pancreatic cancer interact with tumor-associated macrophages, with the goal of identifying actionable therapeutic targets to boosting anti-tumor immunity for the treatment of this disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Using cutting-edge genomic technologies, we have performed a comprehensive analysis of the molecular alterations occurring in cells of the immune system upon infiltration into pancreatic tumors. These data have revealed a unique molecular blueprint of tumor-associated macrophages that is associated to disease progression and poor prognosis. We have found that pancreatic cancer cells produce a class of molecules able to convert macrophages from activators to suppressors of anti-tumor immunity. In preliminary experiments, targeting these molecules was associated to reduced tumor growth and higher immune-mediated tumor rejection in preclinical models of pancreatic cancer. These studies have resulted in publications in major scientific journals and have been presented at international scientific meeting. Finally, results of the project were communicated nationally and internationally via social networks, press releases, and participation to radio broadcasts.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project combined innovative genomic technologies with advanced bioinformatic analyses to uncover novel drivers of pancreatic cancer progression and regulators of the interplay with the immune system. We have uncovered a novel therapeutic target - namely, a specific interplay between macropjahges and tumor cells - whose manipulation in experimental models efficiently limited tumor growth in vivo. These studies have major translational implications as they highlight a novel strategy to modulate immune dynamics in a disease largely resistant to immunotherapies.

Localized interaction between macrophages and tumor cells, fueling disease progression