Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

• Published in: Cancers Vol. 11; no. 12; p. 1832
• Main Authors: Verdeil, Grégory, Lawrence, Toby, Schmitt-Verhulst, Anne-Marie, Auphan-Anezin, Nathalie
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-11-2019; Taylor & Francis; MDPI
• Subjects: Angiogenesis; Breast cancer; Cancer; Cancer therapies; CD8 antigen; Clinical trials; Cytokines; Cytotoxicity; Effector cells; Gene expression; Gene regulation; Genotype & phenotype; Immunological memory; Immunology; Immunotherapy; Inflammation; Kinases; Life Sciences; Lymphocytes; Lymphocytes T; Macrophages; Melanoma; Memory cells; NF-κB protein; Nuclear transport; Recruitment; Review; Signal transduction; Stat3 protein; Stat5 protein; Transcription factors; Tumors; adoptive T cell therapy; immune suppression; inflammation; STAT transcription factors; tumor-associated macrophages
• ISSN: 2072-6694; 0129-797X; 2072-6694
• DOI: 10.3390/cancers11121832

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.