Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes

Abstract

Background Innovative therapies to target tumor-associated neutrophils (PMN) are of clinical interest, since these cells are centrally involved in cancer inflammation and tumor progression. Resolvin D1 (RvD1) is a lipid autacoid that promotes resolution of inflammation by regulating the activity of distinct immune and non-immune cells. Here, using human papilloma virus (HPV) tumorigenesis as a model, we investigated whether RvD1 modulates PMN to reduce tumor progression. Methods Growth-curve assays with multiple cell lines and in vivo grafting of two distinct HPV-positive cells in syngeneic mice were used to determine if RvD1 reduced cancer growth. To investigate if and how RvD1 modulates PMN activities, RNA sequencing and multiplex cytokine ELISA of human PMN in co-culture with HPV-positive cells, coupled with pharmacological depletion of PMN in vivo, were performed. The mouse intratumoral immune cell composition was evaluated through FACS analysis. Growth-curve assays and in vivo pharmacological depletion were used to evaluate anti-tumor activities of human and mouse monocytes, respectively. Bioinformatic analysis of The Cancer Genome Atlas (TCGA) database was exploited to validate experimental findings in patients. Results RvD1 decreased in vitro and in vivo proliferation of human and mouse HPV-positive cancer cells through stimulation of PMN anti-tumor activities. In addition, RvD1 stimulated a PMN-dependent recruitment of classical monocytes as key determinant to reduce tumor growth in vivo. In human in vitro systems, exposure of PMN to RvD1 increased the production of the monocyte chemoattractant protein-1 (MCP-1), and enhanced transmigration of classical monocytes, with potent anti-tumor actions, toward HPV-positive cancer cells. Consistently, mining of immune cells infiltration levels in cervical cancer patients from the TCGA database evidenced an enhanced immune reaction and better clinical outcomes in patients with higher intratumoral monocytes as compared to patients with higher PMN infiltration. Conclusions RvD1 reduces cancer growth by activating PMN anti-cancer activities and encouraging a protective PMN-dependent recruitment of anti-tumor monocytes. These findings demonstrate efficacy of RvD1 as an innovative therapeutic able to stimulate PMN reprogramming to an anti-cancer phenotype that restrains tumor growth.

Aspirin-Triggered Resolvin D1 Reduces Proliferation and the Neutrophil to Lymphocyte Ratio in a Mutant KRAS-Driven Lung Adenocarcinoma Model

“…SPMs that interact with ALX/FPR2 can also regulate the phenotype of tumour-associated macrophages, whereby SAA polarised macrophages support tumour growth, which was suppressed by SPMs [40]. RvD1 can also reduce cancer growth in a manner that was dependent on neutrophils, as depleting neutrophils with an anti-Ly6G antibody markedly suppressed the anti-tumour actions of RvD1 in vivo [41]. They propose that RvD1 reprograms neutrophils to recruit classical monocytes that display anti-cancer actions.…”

Specialized Pro-Resolving Mediators Mitigate Cancer-Related Inflammation: Role of Tumor-Associated Macrophages and Therapeutic Opportunities

“…However, no direct evidence of SPMs’ effects on NF-кB were reported on TAMs so far. Of note, beyond acting on macrophages, SPMs can also modulate other immune cells present in TME such as T- or B-lymphocytes ( 170 ), cancer-associated fibroblasts (CAFs) ( 177 ) or tumor-associated neutrophils (TANs) ( 184 ) to unlock their antitumoral activities.…”

Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled

“…Tumor rejection is achieved by a combined effect of direct anti-tumor activity of neutrophils, neutrophil-induced anti-tumor T cell responses and anti-tumor NK cell activities [ 83 ]. Neutrophils might also modulate the anti-tumor function of macrophages [ 84 ]. However, the simultaneous presence of G-MDSCs that tune down the activities of both cytotoxic T and NK cells might overshadow the anti-tumor neutrophil function in various experimental settings [ 85 , 86 ].…”

“…Factors that can promote the anti-tumor neutrophil phenotype include chemokines (e.g., CXCL2, CXCL5, CXCL8, CCL2, CCL3, CCL5, CXCL12 (SDF-1), CXCL16 and IL-8) alone or together with G-CSF/GM-CSF [ 60 , 61 , 62 , 200 , 201 ], TNFα [ 200 ], IFNβ [ 53 ], IFNγ [ 202 ], IFNγ together with TNFα [ 203 ], Resolvin D1 [ 84 ], hepatocyte growth factor (HGF) [ 168 ] and IL-17 [ 118 ] ( Table 3 ). TNFα, CXCL8 and IFNγ could mobilize the extrinsic apoptosis-promoting TRAIL from intracellular stores to the neutrophil cell surface, which is involved in the killing of cancer cells [ 200 , 202 ].…”