Abstract P11: The elevated level of the main markers of neutrophil extracellular traps in metastatic colorectal cancer plasma highlights the enhanced risk of severe forms of COVID-19 in cancer patients

Abstract Several recent reports have described the involvement of neutrophil extracellular traps (NETs) formation in cancer progression. Moreover, we ourselves were amongst the first to link NETs dysregulation to the COVID-19 pathogenesis1. In response to infection, stimulated neutrophils play an important role as the first line of innate immune defense, by producing extensive extracellular structures composed of granular protein assembled on a scaffold of released chromatin. In addition to mechanically trapping microorganisms, and thus impeding their dissemination in blood, NETs exploits coagulant function to segregate them within the circulation2, while NET by-products such as circulating DNA, histones, granule enzymes (Elastase, Myeloperoxidase,…) also contribute to the triggering of an inflammatory process. As most of the sterile or infectious diseases associated with NET imbalance, cancer is established as a COVID-19 comorbidity. We hypothese that NET formation may result in higher COVID-19 severity. Our objective is to highlight that high NETs formation result in higher COVID-19 severity in cancer patients infected with SARS-Cov2. We are involved in two concurrent clinical studies in which we analyze blood samples for testing NET by-products and formation: (i) in newly diagnosed mCRC patients; and (ii) in patients with intermediate and severe forms of COVID-19. Initial data has shown that the level of the main markers of NETs formation, such as Elastase (ELA2), Myeloperoxidase (MPO), or circulating DNA (cirDNA), are (i) highly correlated in more than 221 mCRC patients, and (ii) statistically (P<0.0001) different than in healthy individuals (N=76). Median concentration values in healthy individuals (n=76): cirDNA: 5,16ng/mL; ELA2: 11,83ng/mL and MPO conc: 12,37ng/mL. Median concentration values in mCRC patients (n=221): cirDNA: 18,36ng/mL; ELA2: 34,70ng/mL and MPO: 38,90ng/mL. CirDNA and MPO or ELA2 concentration do not statistically correlate in healthy individuals, while cirDNA, ELA2 and MPO highly correlate each other (p<0.0001). Since malignant cell derived mutant cirDNA and total cirDNA are similarly correlated with increased level of NET by-products, we speculate that increased tumor burden and increased NET formation are correlated. Thus, NET by-products might be exploited as tumor progression biomarkers which could also be used to guide the choice of immunological therapeutic options. Lastly, our initial data support the hypothesis that cancer-associated NET exacerbation further contributes to COVID-19 severity.1Thierry AR, Roch B. Neutrophil Extracellular Traps and By-Products Play a Key Role in COVID-19: Pathogenesis, Risk Factors, and Therapy. J Clin Med. 2020 Sep 11;9(9):2942. doi: 10.3390/jcm9092942. PMID: 32933031; PMCID: PMC7565044.2Thierry AR. Anti-protease Treatments Targeting Plasmin(ogen) and Neutrophil Elastase May Be Beneficial in Fighting COVID-19. Physiol Rev. 2020 Oct 1;100(4):1597-1598. doi: 10.1152/physrev.00019.2020. PMID: 32639219; PMCID: PMC7365835. Citation Format: Alain R. Thierry, Brice Pastor, Jean-Daniel Abraham, Ekaterina Pisareva, Thibault Mazard. The elevated level of the main markers of neutrophil extracellular traps in metastatic colorectal cancer plasma highlights the enhanced risk of severe forms of COVID-19 in cancer patients [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr P11.