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.
Resources from the same session
51P - Functional characterization of the novel long intergenic non-coding RNA-RFC4, a transcript regulating chromosomal instability in prostate cancer
Presenter: Rogelio Montiel Manríquez
Session: Cocktail & Poster Display session
Resources:
Abstract
52P - The concentration of mutated copies of driver genes in plasma closely mirrors the disease course in colorectal cancer, lung cancer, and melanoma patients
Presenter: Ekaterina Kuligina
Session: Cocktail & Poster Display session
Resources:
Abstract
53P - Heterogeneous characteristics of KRAS mutation subtypes in surgically resected lung adenocarcinomas
Presenter: Kazuya Takamochi
Session: Cocktail & Poster Display session
Resources:
Abstract
54P - ATRX-deficient IDH-wildtype adult high-grade gliomas display novel, clinically relevant genetic patterns by comprehensive genomic profiling
Presenter: Gábor Bedics
Session: Cocktail & Poster Display session
Resources:
Abstract
55P - EGFR variant allele frequency (VAF) impacts on metastatic NSCLC patients outcome during first-line osimertinib
Presenter: Silvia Teresa Riva
Session: Cocktail & Poster Display session
Resources:
Abstract
57P - Clinical characteristics and outcomes in non-small cell lung cancer (NSCLC) with tumour and germline BRCA1/2 mutations
Presenter: Greydon Arthur
Session: Cocktail & Poster Display session
Resources:
Abstract
58P - Molecular investigation using microarray-based comparative genomic hybridization in patients with myelodysplastic syndrome and normal karyotype
Presenter: Mohamed abd naceur AMMAR
Session: Cocktail & Poster Display session
Resources:
Abstract
59P - Unraveling methylation signatures in RAS/BRAF wild-type colorectal cancer patients to identify predictive biomarkers for anti-epidermal growth factor receptor therapy
Presenter: Ana Regina de Abreu
Session: Cocktail & Poster Display session
Resources:
Abstract
60P - Spindle cell sarcomas with tyrosine kinase rearrangement
Presenter: Lenka Krsková
Session: Cocktail & Poster Display session
Resources:
Abstract
61P - Deconvoluting the intra-tumour heterogeneity and subclonal evolution of CDK4/6 inhibitor resistance in ER+ breast cancer
Presenter: Ioanna Mavrommatis
Session: Cocktail & Poster Display session
Resources:
Abstract