The role of neutrophil-released myeloperoxidase in cancer-associated cachexia in patients with pancreatic cancer and in a murine cachexia model.

Abstract

e24096 Background: Cancer-associated muscle wasting (i.e. cachexia) is largely driven by inflammatory mediators and affects most patients with gastrointestinal cancers. Elevated neutrophil counts have been demonstrated in cachectic patients and preclinical models. Neutrophils exert their catabolic effects through the release of peroxidases, namely myeloperoxidase (MPO). Interestingly, MPO inhibitors have shown promising results in mitigating atherosclerosis (NCT03611153); however, their ability to mitigate cachexia has not been investigated. The purpose of this study was to determine the role of MPO in cachexia progression in pancreatic cancer patients and a murine cachexia model. Methods: Serum was collected from 49 patients with locally advanced or metastatic pancreatic cancer at Atrium Health Levine Cancer within the Atrium Health Wake Forest Baptist Comprehensive Cancer Center. Patients were separated into 2 groups based on body weight (BW) loss within 3-months of diagnosis (WS: < 5% BW loss; CX: ≥5% BW loss). Additionally, publicly available SKM CD45+ cell scRNAseq of pancreatic cancer patients was re-analyzed. Proteomic analyses of patient serum are ongoing and will assess cachexia-related cytokines (MPO, TNFα, IL-6, IL-1β, Leptin, GDF-15, IGF-1, P-Selectin, TNFS14, and CCL2). CD2F1 mice were implanted with 10^6 cachexia-inducing C26 or heat-killed tumor cells. Results: Among 49 patients (22 without cachexia, 27 with cachexia), baseline demographic and clinical characteristics were similar between groups (all p > 0.05). Mean age was 64 vs 67 years, and half were female. Most patients were White/Caucasian (74%) and Non-Hispanic/Latinx (98%). Disease stage was similarly advanced in both groups, with 76% with stage IV disease at diagnosis. Preliminary data demonstrated a trend toward higher circulating MPO levels in CX patients (WS: 25.35 ± 11.4 ng/mL; CX: 29.57 ± 11.1 ng/mL, p = 0.10). CD45+ scRNAseq of patients revealed 3 transcriptionally distinct neutrophil subclusters in SKM, characterized as 1) inflammatory/invasive, 2) immunosuppressive, and 3) “aged” N2-like. Similarly, cachectic mice (-10% BW loss, p = 0.017) had significantly higher circulating MPO levels compared to non-tumor mice (167.2 ± 49.3 ng/mL vs. 33.21 ± 1.5 ng/mL; p = 0.01), with increased SKM neutrophils (9.3-fold; p < 0.01) with markedly elevated MPO gene expression ( > 17-fold) and elevated SKM MPO protein expression (3.9-fold; p = 0.01). Conclusions: These findings suggest an association between MPO and cancer cachexia in pancreatic cancer patients and a murine cachexia model. Together, these findings support MPO as a biologically plausible therapeutic target, pending ongoing mechanistic studies.