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

Cocktail & Poster Display session

85P - Whole-genome CRISPR screening identifies chemosensor receptors as key regulators of the cancer-macrophage crosstalk

Date

04 Oct 2023

Session

Cocktail & Poster Display session

Presenters

Giulia Marelli

Citation

Annals of Oncology (2023) 8 (suppl_1_S5): 1-55. 10.1016/esmoop/esmoop101646

Authors

G. Marelli1, N. Morina2, M. Iovino2, S. Puccio2, M. Carvetta2, L. Morosi2, G. Martano2, E. Paraboschi2, M. Lazzeri2, P. Colombo2, P. Casale2, C. Peano2, S. Marchini3, E. Lugli2, D. Di Mitri1

Author affiliations

  • 1 Via Rita Levi Montalcini, 4, IRCCS Humanitas Research Hospital, 20089 - Rozzano/IT
  • 2 IRCCS Humanitas Research Hospital, 20089 - Rozzano/IT
  • 3 Cancer Pharmacology, Humanitas Research Hospital, 20089 - Rozzano/IT

Resources

This content is available to ESMO members and event participants.

Abstract 85P

Background

Tumor-associated macrophages (TAMs) are known to support tumor growth and progression in multiple cancers, including prostatic adenocarcinoma (PCa). However, the mechanisms behind macrophage re-education by cancer cells are still mostly unknown. Main aim of this project is to dissect the mechanisms utilised by the tumour to train macrophages in its favour. Our final purpose is to find molecular targets that may be exploited to develop novel immunotherapies or more efficient combinatorial approaches for the treatment of cancer.

Methods

We employed a genome wide CRISPRi screening to tumour-conditioned macrophages, with the aim of identifying targets capable of reverting macrophage activation toward an anti-tumour state. We then validated the results of the library using multiparametric Flow Cytometry analysis and immunofluorescence assays and we employed mouse models of prostate cancer to test in vivo promising targets identified by the screening.

Results

We identified a group of genes that codify for chemosensor receptors and act as regulators of pro-tumoral functions in TAMs. Genetic deletion of selected chemosensors re-educates CD206bright MHC-IIneg pro-tumoral macrophages and confer to these cells a CD206negMHC-IIbright pro-inflammatory phenotype. Functionally, chemosensors depleted macrophages (chemKO Macs) supported CD8+ cell proliferation and inhibited migration of tumour cells in vitro. In vivo, administration of chemKO Macs to tumour bearing mice resulted in a reduced tumour growth. Moreover, tumours from mice injected with chemKO Macs showed an altered tumour microenvironment enriched in tumour specific CD8+ CD39+ T cells. Additionally, we detected the expression of the chemosensor receptor OR51E2 on primary human macrophages in vitro and in tumor-infiltrating macrophages in tissues from PCa patients, therefore recapitulating our findings in a human setting. Finally, we identified palmitic acid as a ligand of OR51E2 and we confirmed its expression in human biopsies from PCa patients.

Conclusions

Our results identified novel targets that could be manipulated to re-educate the macrophage compartment in PCa.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Associazione Italiana per la Ricerca sul cancro (AIRC).

Disclosure

All 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.