Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression

Abstract

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.

Antigen-Specific Immunity and Cross-Priming by Epithelial Ovarian Carcinoma-Induced CD11b+Gr-1+ Cells

“…Although it was anticipated that this population would comprise immunosuppressive MDSCs, our results were not consistent with previous studies (20)(21)(22). This population did not represent vascular leukocyte cells based on either phenotypic or functional differences (23)(24)(25). In addition, these CD11b + Gr-1 + cells stimulated Ag-nonspecific and Ag-specific T cells both in vitro and in vivo.…”

“…pp , 0.05; ppp , 0.01; pppp , 0.0005; ppppp , 0.0001. inconsistencies in the scientific literature (30,34,35). Nonetheless, our data demonstrate that the CD11b + Gr-1 + cells in ID8/ascites are distinct from any known subpopulation of MDSCs or vascular leukocyte cells (CD11c + CD11b + Gr-1 + CD31 + CD115 + F4/80 + ) (24,25) described to date. In addition, CD3 expression (Supplemental Fig.…”

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

“…Tumor-derived PgE2 was the main inducer of arginase I in regDCs and arginase I played the major role in suppressing CD4+ T cell response by regDCs [13]. Expression of arginase 1 in regDCs might cause dysregulation of the T cell receptor (TCR) signal and subsequently induces CD8+ T cell unresponsiveness [65]. T cell responses are profoundly suppressed by myeloid cell arginase-mediated L-arginine depletion and this has emerged as a fundamental mechanism of inflammationassociated immunosuppression [66].…”

Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent

“…An important mechanism through which cancers escape immune destruction is via recruitment or induction of suppressor immune cells, including regulatory T cells (Treg) and myeloidderived suppressor cells (MDSC) (20)(21)(22). Human MDSC are a heterogeneous population of immature myeloid cells that inhibit T cell effector function through a range of mechanisms, such as arginase-1 and inducible nitric oxide synthase (23)(24)(25). While rare in healthy individuals, MDSC may accumulate in the settings of severe trauma, sepsis, or cancer (26).…”