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.
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