title: Neem leaf glycoprotein regulates function of tumor associated M2 macrophages in hypoxic tumor core: Critical role of IL-10/STAT3 signaling.
abstract: Heterogeneous tumor microenvironment (TME), broadly divided into tumor core and peripheral sub-microenvironments, differentially polarize normal macrophages into a different form known as tumor associated M2 macrophages (M2TAMs) to promote tumor growth. In view of the extensive immune-editing role of NLGP, here, we have observed that NLGP is effective to convert M2TAMs (CD11b+F4/80high) to M1 (CD11b+F4/80low) more prominently in tumor core, along with downregulation of other M2 associated markers, like, ManR, Ym1, Fizz1. High IL-10:IL-12 ratio at tumor core was downregulated in NLGP treated melanoma bearing mice. Decrease in IL-10 by NLGP is again associated with the decrease in hypoxia, as indicated by prominent downregulation of HIF1α and VEGF, particularly at tumor core. Macrophages exposed to hypoxic tumor core lysates in vitro exhibited high IL-10, HIF1α and VEGF expression that was significantly downregulated by NLGP. Further evidences suggest M2TAM to M1 conversion by NLGP is associated with STAT3-regulated IL-10 dependent pathway without affecting the IL-4 dependent one. Such TAM modulatory functions of NLGP might help in the restriction of melanoma growth by increasing the proportion of M1 TAMs in tumor core that helps in prevention of tumor relapse and dissemination of the tumor mass.
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Kuntal Kanti
authors: KK
authors: Goswami
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Madhurima
authors: M
authors: Sarkar
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Sarbari
authors: S
authors: Ghosh
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Akata
authors: A
authors: Saha
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Tithi
authors: T
authors: Ghosh
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Ipsita
authors: I
authors: Guha
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Subhasis
authors: S
authors: Barik
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Saptak
authors: S
authors: Banerjee
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Soumyabrata
authors: S
authors: Roy
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Anamika
authors: A
authors: Bose
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India.
authors: Parthasarathi
authors: P
authors: Dasgupta
authors: Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata 700026, India. Electronic address: baralrathin@hotmail.com.
authors: Rathindranath
authors: R
authors: Baral
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D031601:Azadirachta; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000187:drug effects; D005434:Flow Cytometry; D006023:Glycoproteins / Q000494:pharmacology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010936:Plant Extracts / Q000494:pharmacology; D018515:Plant Leaves; D010940:Plant Proteins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006023:Glycoproteins; C556062:IL10 protein, mouse; D010936:Plant Extracts; D010940:Plant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016753:Interleukin-10
keywords: IL-10; Neem leaf glycoprotein; STAT3; Tumor associated macrophages; Tumor microenvironment