title: HPV16 tumor associated macrophages suppress antitumor T cell responses.
abstract: OBJECTIVE
  High-risk human papillomavirus (HPV) is the main etiologic factor for cervical cancer. The severity of HPV-associated cervical lesions has been correlated to the number of infiltrating macrophages. The objective of this work is to characterize the role of tumor-associated macrophages (TAM) on the immune cellular response against the tumor.
  
  
  METHODS
  We used the HPV16 E6- and E7-expressing TC-1 mouse tumor model to study the effect of TAM on T-cell function in vitro, and depleted TAM, using clodronate-containing liposomes, to characterize its role in vivo.
  
  
  RESULTS
  TAM, characterized by the positive expression of CD45, F4/80, and CD11b, formed the major population of infiltrating tumor cells. TAM displayed high basal Arginase I activity, producing interleukin-10 (IL-10); they were resistant to iNOSII activity induction, therefore reversion to M1 phenotype, when stimulated in vitro with lipopolysaccharide/IFNgamma, indicating an M2 phentoype. In cultures of isolated TAM, TAM induced regulatory phenotype, characterized by IL-10 and Foxp3 expression, and inhibited proliferation of CD8 lymphocytes. In vivo, depletion of TAM inhibited tumor growth and stimulated the infiltration of tumors by HPV16 E7(49-57)-specific CD8 lymphocytes, whereas depletion of Gr1(+) tumor-associated cells had no effect.
  
  
  CONCLUSIONS
  M2-like macrophages infiltrate HPV16-associated tumors causing suppression of antitumor T-cell response, thus facilitating tumor growth. Depletion or phenotype alteration of this population should be considered in immunotherapy strategies.
authors: Laboratory of Virology Ludwig Institute for Cancer Research, São Paulo branch, Rua João Julião, 245, São Paulo, SP, Brazil. alepique@ludwig.org.br
authors: Ana Paula
authors: AP
authors: Lepique
authors: Katia Regina Perez
authors: KR
authors: Daghastanli
authors: Iolanda Midea
authors: IM
authors: Cuccovia
authors: Luisa Lina
authors: LL
authors: Villa
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D051379:Mice; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000209:etiology / Q000276:immunology* / Q000473:pathology
chemical_list: D000943:Antigens, Differentiation; D039481:CD11b Antigen; C036763:monocyte-macrophage differentiation antigen; D017493:Leukocyte Common Antigens; D001119:Arginase