Silence STAT3 in the procancer niche…and activate CD8⁺ T cells to kill premetastatic myeloid intruders

Abstract

To efficiently counter tumor development, CD8 + T cells need to be activated in the tumor draining lymph node (TDLN) by DCs presenting tumor antigen (TA), a process that requires the capacity of DCs to "cross-present" the TA. In addition, the DCs need to be induced to differentiate into the appropriate stimulatory mode, with high expression of costimulatory molecules and MHC molecules (reviewed in [1]). If this initial interaction between the DC and the CD8 + T cell is successful, the CD8 + T cells to which the TA is presented subsequently differentiate into CTLs and acquire expression of effector molecules such as granzyme B and perforin, Correspondence: Dr. Anne-Marie Schmitt-Verhulst e-mail: verhulst@ciml.univ-mrs.fr the capacity to produce IFN-γ and also express surface molecules that permit their migration toward the tumor site. Although evidence for the successful elimination of primary tumors by CD8 + T cells exists in some experimental settings, as exemplified by the immunoediting occurring in chemically induced carcinomas in mice [2], in most cases T cells are ineffective at clearing tumors, notably as a result of the multiple immunosuppressive pathways present in the tumor environment [3,4].Recent evidence suggests a major role for the activation of the "transcription factor signal transducer and activator of transcription 3" (STAT3) in the induction and maintenance of a procarcinogenic, immunosuppressive tumor microenvironment (reviewed in [5]). In particular, oncogene-induced production of inflammatory mediators (such as IL-6, IL-10, and VEGF) by the tumor itself promotes STAT3 activation, causing an increase in both tumor proliferation and survival, and tumor-derived inflammatory cytokines (such as IL-6, -10, -11, -17, -21, -23; VEGF) that constitute STAT3 amplifying loops that further shape the tumor microenvironment [5,6]. One such amplifying loop comprises the recruitment and expansion of myeloid-derived cells with immune-suppressive activity to the microenvironment, which has been shown to be critical for disease progression and resistance to therapy [7,8]. These immune-suppressive, myeloid-derived cells are an heterogeneous population of immature myeloid cells that normally develop as intermediates during myelopoiesis in the bone marrow, but which were found to accumulate in certain pathological situations including cancer in both humans and mice [9,10]. Inhibition of T-cell function by immune-suppressive, myeloid-derived cells has been shown to be mediated by several mechanisms, including expression of enzymes affecting amino acid metabolism, such as the expression of arginase I by blood-derived myeloid cells in breast cancer patients [9,10]. Additionally, several studies have implicated soluble factors (VEGF, TGF-β, S100 inflammatory chemokines) secreted by the primary tumor in the recruitment of VEGFR1 + bone marrowderived hematopoietic progenitor cells [11] and Mac1 + myeloid cells [12] thereby providing an optimal "soil" for tumor cells to survive and to colonize secondary sites for metast...

Interplay of DNA methyltransferase 1 and EZH2 through inactivation of Stat3 contributes to β-elemene-inhibited growth of nasopharyngeal carcinoma cells

“…As evidence by our findings that exogenously expressed Stat3 overcame the effect of β-elemene on NPC cell proliferation implied the important role of this transcription factor inactivation in mediating the anti-NPC responses. Overexpression of Stat3 has been shown to resist the anti-cancer effects, resulting in poor prognosis in several malignancies 30, 47–51 . Thus, Stat3 not only provided a potential mechanism of action for tyrosine kinase inhibitors but also represented new molecular targets for novel NPC therapy.…”

Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy

“…In addition to the role in vasculogenesis, MMP also play a role in promoting tumor cell metastasis. Furthermore, MDSCs expressing active STAT3 have been implicated in the formation of pre-metastatic niches [137], [138]. These cells condition organs by creating an immunosuppressive environment that allows growth of metastatic tumor cells [139–141].…”

“…However, activation of STAT3 compromises the ability of T cells to kill MDSCs [137], [138]. This was linked to lower granzyme B expression by CD8 + T cells and resistance of MDSCs to T-cell killing.…”