title: Immunostimulatory early phenotype of tumor-associated macrophages does not predict tumor growth outcome in an HLA-DR mouse model of prostate cancer.
abstract: Tumor-associated macrophages (TAM) were shown to support the progression of many solid tumors. However, anti-tumor properties of TAM were also reported in several types of cancer. Here, we investigated the phenotype and functions of TAM in two transgenic mouse models of prostate cancer that display striking differences in tumor growth outcome. Mice expressing prostate-specific antigen (PSA) as a self-antigen specifically in prostate (PSAtg mice) rejected PSA-expressing transgenic adenocarcinoma of mouse prostate (TRAMP) tumors. However, the introduction of HLA-DRB1*1501 (DR2b) transgene presenting PSA-derived peptides in a MHC class II-restricted manner exacerbated the growth of TRAMP-PSA tumors in DR2bxPSA F 1 mice. Despite the difference in tumor growth outcome, tumors in both strains were equally and intensively infiltrated by macrophages on the first week after tumor challenge. TAM exhibited mixed M1/M2 polarization and simultaneously produced pro-inflammatory (TNFα, IL1β) and anti-inflammatory (IL10) cytokines. TAM from both mouse strains demonstrated antigen-presenting potential and pronounced immunostimulatory activity. Moreover, they equally induced apoptosis of tumor cells. In vivo depletion of macrophages in DR2bxPSA F 1 but not PSAtg mice aggravated tumor growth suggesting that macrophages more strongly contribute to anti-tumor immunity when specific presentation of PSA to CD4+ T cells is possible. In summary, we conclude that in the early stages of tumor progression, the phenotype and functional properties of TAM did not predict tumor growth outcome in two transgenic prostate cancer models. Furthermore, we demonstrated that during the initial stage of prostate cancer development, TAM have the potential to activate T cell immunity and mediate anti-tumor effects.
authors.affiliation: Department of Surgery, Division of Urology, University of Maryland, 10S Pine Street, MSTF-4, Baltimore, MD, 21201, USA, vbryabov@mail.ru.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Riabov
authors.forename: David
authors.initials: D
authors.lastname: Kim
authors.forename: Surmeet
authors.initials: S
authors.lastname: Chhina
authors.forename: Richard B
authors.initials: RB
authors.lastname: Alexander
authors.forename: Elena N
authors.initials: EN
authors.lastname: Klyushnenkova
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D017430:Prostate-Specific Antigen / Q000276:immunology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017430:Prostate-Specific Antigen