title: Neem leaf glycoprotein inhibits CD4+CD25+Foxp3+ Tregs to restrict murine tumor growth.
abstract: BACKGROUND
  The presence of Tregs in tumors is associated with compromised tumor-specific immune responses and has a clear negative impact on survival of cancer patients. Thus, downregulation of Tregs is considered as a promising cancer immunotherapeutic approach. We have reported previously that neem leaf glycoprotein (NLGP) prophylaxis restricts tumor growth in mice by immune activation. In continuation, here, involvement of NLGP in the modulation of Tregs in association with tumor growth restriction is investigated.
  
  
  RESULTS
  NLGP downregulates CD4+CD25+Foxp3+ Tregs within tumors. NLGP-mediated downregulation of CCR4 along with its ligand CCL22 restricts Treg migration at the tumor site. NLGP is not apoptotic to Tregs but significantly downregulates the expression of Foxp3, CTLA4 and GITR. It also reverses the functional impairment of T-effector cells by Tregs, in terms of IFN-γ secretion, cellular proliferation and tumor cell cytotoxicity. NLGP also facilitates reconditioning of tumor microenvironment (hostile) by increasing IFN-γ and IL-12 but decreasing IL-10, TGF-β, VEGF and IDO, creating an antitumor niche. Interaction between Foxp3, p-NFATc3 and p-Smad2/3, needed for successful Treg function, is also inhibited by NLGP.
  
  
  CONCLUSIONS
  All of these coordinated events might result in inhibition of Treg associated-tumor growth and therefore increased survivability of mice having NLGP treatment before or/and after tumor inoculation. Thus, the possibility of NLGP being an excellent tool as a T-cell anergy breaker by abrogating the suppressor functions of Tregs in cancer needs to be explored further in the clinic.
authors.affiliation: Department of Immunoregulation & Immunodiagnostics, Chittaranjan National Cancer Institute (CNCI), 37 SP Mukherjee Road, Kolkata 700026, India.
authors.forename: Tathagata
authors.initials: T
authors.lastname: Chakraborty
authors.forename: Anamika
authors.initials: A
authors.lastname: Bose
authors.forename: Subhasis
authors.initials: S
authors.lastname: Barik
authors.forename: Kuntal Kanti
authors.initials: KK
authors.lastname: Goswami
authors.forename: Saptak
authors.initials: S
authors.lastname: Banerjee
authors.forename: Shyamal
authors.initials: S
authors.lastname: Goswami
authors.forename: Diptendu
authors.initials: D
authors.lastname: Ghosh
authors.forename: Soumyabrata
authors.initials: S
authors.lastname: Roy
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chakraborty
authors.forename: Koustav
authors.initials: K
authors.lastname: Sarkar
authors.forename: Rathindranath
authors.initials: R
authors.lastname: Baral
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D031601:Azadirachta; D018956:CD5 Antigens / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054422:Chemokine CCL22 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006023:Glycoproteins / Q000008:administration & dosage* / Q000009:adverse effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018515:Plant Leaves; D010940:Plant Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D054398:Receptors, CCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D018956:CD5 Antigens; C515355:Ccr4 protein, mouse; D054422:Chemokine CCL22; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; D053645:Interleukin-2 Receptor alpha Subunit; D010940:Plant Proteins; D054398:Receptors, CCR4