title: Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine.
abstract: Macrophages are projected as one of the key players responsible for the progression of cancer. Classically activated (M1) macrophages are pro-inflammatory and have a central role in host defense, while alternatively activated (M2) macrophages are associated with immunosuppression. Macrophages residing at the site of neoplastic growth are alternately activated and are referred to as tumor-associated macrophages (TAMs). These "cooperate" with tumor tissue, promoting increased proliferation and immune escape. Selective serotonin reuptake inhibitors like fluoxetine have recently been reported to possess anti-inflammatory activity. We used fluoxetine to target tumor-associated inflammation and consequent alternate polarization of macrophages. We established that murine peritoneal macrophages progressed towards an altered activation state when exposed to cell-free tumor fluid, as evidenced by increased IL-6, IL-4 and IL-10 levels. These polarized macrophages showed significant pro-oxidant bias and increased p65 nuclear localization. It was further observed that these altered macrophages could induce oxidative insult and apoptosis in cultured mouse CD3(+) T cells. To validate these findings, we replicated key experiments in vivo, and observed that there was increased serum IL-6, IL-4 and IL-10 in tumor-bearing animals, with increased % CD206(+) cells within the tumor niche. TAMs showed increased nuclear localization of p65 with decreased Nrf2 expression in the nucleus. These results were associated with increase in apoptosis of CD3(+) T cells co-cultured with TAM-spent media. We could establish that fluoxetine treatment could specifically re-educate the macrophages both in vitro and in vivo by skewing their phenotype such that immune suppression mediated by tumor-dictated macrophages was successfully mitigated.
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India.
authors.forename: Sayan
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India.
authors.forename: Sreetama
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India.
authors.forename: Payal
authors.initials: P
authors.lastname: Gupta
authors.affiliation: Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata-700098, India.
authors.forename: Arghya
authors.initials: A
authors.lastname: Adhikary
authors.affiliation: Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata-700026, India.
authors.forename: Rathindranath
authors.initials: R
authors.lastname: Baral
authors.affiliation: Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata-700098, India. Electronic address: sreyachatterjee@yahoo.com.
authors.forename: Sreya
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D005473:Fluoxetine / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D016207:Cytokines; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D005473:Fluoxetine
keywords: Fluoxetine; Immunosuppression; Inflammation; Macrophage polarization; Tumor