Abstract
Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients.
Highlights
Inflammation is considered as a hallmark of cancer [1] and the inflammatory context in many cancers is strongly linked to poor prognosis and resistance to therapy
The frequency of tumor-specific CD8 T cells can be increased in cancer patients through sophisticated personalized medical approaches including in vitro derived and expanded tumor-infiltrating lymphocytes (TILs) or engineered Chimeric Antigenic Receptor (CAR)-T cells
The ability of adoptively transferred T cells to survive in cancer-invaded hosts and to efficiently penetrate into the tumor are dampened by the solid tumor landscape including cancer cells, tumor stroma and immune suppressive myeloid cells
Summary
Inflammation is considered as a hallmark of cancer [1] and the inflammatory context in many cancers is strongly linked to poor prognosis and resistance to therapy. Differential signal transduction pathways downstream of cell surface sensors define gene expression programs underlying anti- or pro- tumor functions of macrophages [18,19]. We recently showed that ovarian cancer cells reprogram macrophages towards an IL-4/AKT/STAT6-mediated tumor-promoting phenotype through increased cholesterol efflux from the TAM membrane [24]. We recently reported [13] that a subset of mature CD163+ TAM present in mouse melanomas, CD163+ macrophages expressing phospho-STAT3 have been observed in human skin tumors [23]. Targeted-depletion of this minor CD163 TAM subset enhanced melanoma-infiltration by CD8 T cells macrophages expressing phospho-STAT3 have been observed in human skin tumors [23].
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