Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression.
The predominant leukocyte population present in both human and murine peritoneal ovarian tumors is the Vascular Leukocyte (VLC). VLCs are recruited en masse to the ovarian tumor microenvironment whereupon they promote tumor progression. Importantly, the presence of VLCs is requisite for peritoneal ovarian cancer progression: selective elimination of VLCs inhibits tumor burden and ascites accumulation. Despite the critical importance of VLCs to ovarian tumors, their derivation and the mechanisms by which they facilitate tumor progression are not well understood. Here we demonstrate in vivo that the murine ID8 ovarian tumor model can usurp the host peritoneal macrophage pathway to elicit and recruit VLCs. Moreover, we demonstrate that VLCs express CD11b and Gr-1, a characteristic phenotype shared amongst heterogeneous populations of leukocytes referred to as myeloid-derived suppressor cells (MDSCs). In accord with their MDSC phenotype, both murine and human VLCs express arginase-1 (ARG1). Importantly, we demonstrate that the VLCs suppress both CD8(+) and CD4(+) T cells responses and that this immunosuppression is ARG1-dependent, since blockade of VLC ARG1 activity with nor-NOHA reversed the immunosuppression. These data further characterize the tumor-associated leukocytes in ovarian cancer and provide insights into the mechanisms by which they promote tumor growth.
Bak
S Peter
SP
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03755, United States.
Alonso
Anselmo
A
Turk
Mary Jo
MJ
Berwin
Brent
B
D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D039481:CD11b Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007962:Leukocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D001119:Arginase