HPV16 tumor associated macrophages suppress antitumor T cell responses.
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.
Lepique
Ana Paula
AP
Laboratory of Virology Ludwig Institute for Cancer Research, São Paulo branch, Rua João Julião, 245, São Paulo, SP, Brazil. alepique@ludwig.org.br
Daghastanli
Katia Regina Perez
KR
Cuccovia
Iolanda Midea
IM
Villa
Luisa Lina
LL
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
D000943:Antigens, Differentiation; D039481:CD11b Antigen; C036763:monocyte-macrophage differentiation antigen; D017493:Leukocyte Common Antigens; D001119:Arginase