PMID- 33845864 OWN - NLM STAT- MEDLINE DCOM- 20211119 LR - 20211119 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 40 IP - 1 DP - 2021 Apr 12 TI - Resolvin D1 reduces cancer growth stimulating a protective neutrophil-dependent recruitment of anti-tumor monocytes. PG - 129 LID - 10.1186/s13046-021-01937-3 [doi] LID - 129 AB - 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. FAU - Mattoscio, Domenico AU - Mattoscio D AUID- ORCID: 0000-0002-2149-2855 AD - Department of Medical, Oral, and Biotechnology Science, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. d.mattoscio@unich.it. AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. d.mattoscio@unich.it. FAU - Isopi, Elisa AU - Isopi E AD - Department of Medical, Oral, and Biotechnology Science, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. FAU - Lamolinara, Alessia AU - Lamolinara A AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. AD - Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. FAU - Patruno, Sara AU - Patruno S AD - Department of Medical, Oral, and Biotechnology Science, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. FAU - Medda, Alessandro AU - Medda A AD - Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy. FAU - De Cecco, Federica AU - De Cecco F AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. AD - Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. FAU - Chiocca, Susanna AU - Chiocca S AD - Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy. FAU - Iezzi, Manuela AU - Iezzi M AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. AD - Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. FAU - Romano, Mario AU - Romano M AD - Department of Medical, Oral, and Biotechnology Science, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. FAU - Recchiuti, Antonio AU - Recchiuti A AD - Department of Medical, Oral, and Biotechnology Science, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. a.recchiuti@unich.it. AD - Center for Advanced Studies and Technology (CAST), University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy. a.recchiuti@unich.it. LA - eng PT - Journal Article DEP - 20210412 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (resolvin D1) RN - 25167-62-8 (Docosahexaenoic Acids) SB - IM MH - Animals MH - Docosahexaenoic Acids/pharmacology/*therapeutic use MH - Humans MH - Mice MH - Monocytes/*metabolism MH - Neoplasms/*blood/*drug therapy MH - Neutrophils/*metabolism PMC - PMC8040222 OTO - NOTNLM OT - Classical monocytes OT - HPV cancers OT - Neutrophils OT - Resolution of inflammation OT - Resolvin D1 COIS- The authors declare that they have no competing interests. EDAT- 2021/04/14 06:00 MHDA- 2021/11/20 06:00 PMCR- 2021/04/12 CRDT- 2021/04/13 05:36 PHST- 2021/01/12 00:00 [received] PHST- 2021/04/03 00:00 [accepted] PHST- 2021/04/13 05:36 [entrez] PHST- 2021/04/14 06:00 [pubmed] PHST- 2021/11/20 06:00 [medline] PHST- 2021/04/12 00:00 [pmc-release] AID - 10.1186/s13046-021-01937-3 [pii] AID - 1937 [pii] AID - 10.1186/s13046-021-01937-3 [doi] PST - epublish SO - J Exp Clin Cancer Res. 2021 Apr 12;40(1):129. doi: 10.1186/s13046-021-01937-3.