STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Abstract

It is well established that tumor progression is associated with the accumulation of myeloid suppressive cells, which in mice include Gr-1+ immature myeloid cells and F4/80+ macrophages. The paradox is that with the exception of terminal stages of the disease or chemotherapy treatment, tumor-bearing mice or cancer patients do not display a profound systemic immune suppression. We therefore raised the question as to whether myeloid cell-mediated T cell suppression is controlled at a local level at the site of the tumor. We have demonstrated that after adoptive transfer to tumor-bearing recipients, Gr-1+ (immature myeloid cells) freshly isolated from spleens of tumor-bearing mice become F4/80+ tumor-associated macrophages (TAM). These TAM, but not F4/80+ macrophages or Gr-1+ cells freshly isolated from spleens of tumor-bearing or naive mice were able to inhibit T cell-mediated immune response in vitro via induction of T cell apoptosis. Arginase and NO were both responsible for the apoptotic mechanism, and were seen only in TAM, but not in freshly isolated Gr1+ cells. Using the analysis of STAT activity in combination with STAT knockout mice, we have determined that STAT1, but not STAT3 or STAT6, was responsible for TAM-suppressive activity.

Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

“…inhibit a T-cell-mediated immune response controlled by STAT1 (Kusmartsev and Gabrilovich, 2005). Moreover, the in vivo ablation of CD11c þ dendritic cells in diphtheria-toxin transgenic mice abrogates priming of cytotoxic T-lymphocyte precursors in immune responses to cell-associated antigens, a phenomenon called cross-priming (Jung et al, 2002).…”

Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

“…Furthermore, STAT1 and STAT3 were involved in hyperoxia-induced gene transcription of HO-1 in RAW 264.7 macrophages (Lee et al, 2000). Activation of STATs presumably plays an important role in establishing the M2 macrophage phenotype in the tumor setting, because STAT1 is constitutively active in TAMs (Biswas et al, 2006) and its enhanced signaling properties mediate T cell deletion (Kusmartsev and Gabrilovich, 2005). Also, STAT3 and STAT6 are believed to contribute to M2 macrophage polarization (Sica and Bronte, 2007).…”

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

“…The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11]? How do MDSC relate to monocyte and macrophage subsets or differentiation stages, such as the Tie2 + monocytes [12], tumour-associated macrophages Commentary and, more generally, polarized M2 macrophages [13]?…”

“…The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”