2293P - Protumoral role of neutrophils and neutrophils extracellular traps (NETS) in non-metastatic gastroesophageal and rectal cancers

Background

Neutrophil extracellular traps (NETs) are structures released by activated neutrophils (NEU) into the extracellular microenvironment in response to different stimuli through a process referred to as NETosis. Although first described as an antimicrobial response to infection, NETosis is also involved in cancer. In the context of gastrointestinal tumors, the enrichment of NETs in the metastatic site (even before tumor cell seeding) compared to primary tumor, along with their capability to entrap disseminated cancer cells, suggest that NETs may serve as scaffolds for microbes or circulating tumor cells to create the metastatic niche. While providing mechanistic insights on the selective liver-tropism of certain cancers, NETs could be developed into a prognostic and predicitve biomarker.

Methods

We prospectively collected serum samples from 137 pts, of which 74 were diagnosed with resectable gastroesophageal adenocarcinoma (GEA) and 63 with locally advanced rectal cancer (LARC). Pts received a multimodal treatment (chemotherapy in GEA cohort or chemoradioterapy in LARC cohort, followed by surgery). Whenever available, paired tissue samples from tumor and non-tumor adjacent tissues were collected at baseline and at surgical time for in-sito NET detection and transcriptomic analysis. Serum samples (n= 372) were collected longitudinally and the NETs quantified by an established ELISA assay for citrullinate histone H3 (cit-H3).

Results

We preliminarly quantified serum NETs of pts in GEA cohort (at baseline, during treatment and at disease progression) showing that cit-H3 levels are positively correlated with tumor burden. Moreover, treatment in vitro of freshly isolated human NEU with interstitial fluids from tumor and non-tumor adjacent tissues revealed the specific influence of tumor microenvironment’s factors on NETs formation. Here, we will present final results obtained on the whole cohort, both on the quantification of circulating NETs and in the tissue of primary and metastatic lesions.

Conclusions

Peripheral NETs positively correlate with tumor burden in the serum of pts with GEA, supporting the relevance of NETosis in tumor progression and their potential as non-invasive biomarker.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Istituto Europeo di Oncologia.

Funding

Has not received any funding.

Disclosure

D. Ciardiello: Financial Interests, Personal, Other, Travel support: Sanofi, BMS; Financial Interests, Personal, Other, Travel Support: Merck Serono. F. Spada: Financial Interests, Personal, Advisory Board: Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, Merck Sharp & Dohme; Financial Interests, Institutional, Advisory Board: GETNE, Incyte, MSD. N. Fazio: Financial Interests, Personal, Advisory Board: AAA, Hutchinson Medi Pharma, MSD, Novartis; Financial Interests, Institutional, Advisory Board: 4SC; Financial Interests, Institutional, Local PI: Astellas, Beigene, FibroGen, Incyte, Ipsen, MSD; Financial Interests, Institutional, Research Grant: Ipsen. C.A. Cella: Financial Interests, Personal, Speaker, Consultant, Advisor, Consultant: BMS; Financial Interests, Personal, Invited Speaker: Leo Pharma; Financial Interests, Institutional, Local PI: Daiichi Sankyo, Novartis; Financial Interests, Institutional, Research Grant: Ipsen. All other authors have declared no conflicts of interest.