Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells

Abstract

Although tumor progression involves processes such as tissue invasion that can activate inflammatory responses, the immune system largely ignores or tolerates disseminated cancers. The mechanisms that block initiation of immune responses during cancer development are poorly understood. We report here that constitutive activation of Stat-3, a common oncogenic signaling pathway, suppresses tumor expression of proinflammatory mediators. Blocking Stat-3 in tumor cells increases expression of proinflammatory cytokines and chemokines that activate innate immunity and dendritic cells, leading to tumor-specific T-cell responses. In addition, constitutive Stat-3 activity induces production of pleiotropic factors that inhibit dendritic cell functional maturation. Tumor-derived factors inhibit dendritic cell maturation through Stat-3 activation in progenitor cells. Thus, inhibition of antitumor immunity involves a cascade of Stat-3 activation propagating from tumor to dendritic cells. We propose that tumor Stat-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.

Signal Transducer and Activator of Transcription 3 (Stat3C) Promotes Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis

“…It has been reported that tumor Stat3 activity promotes production of VEGF and IL-10. 29 Ablating Stat3 in hema- A representative flow cytometry analysis shows decreased CD69 ϩ expression on splenic CD4 ϩ T cells. The frequency of CD69 ϩ expression was statistically analyzed (mice, n ϭ 5).…”

Stat3 activation in human endometrial and cervical cancers

“…There are about 10 370 new cases of invasive cervical cancer in the United States and about 3710 women will die from this disease. Constitutive Stat3 signaling appears to play a role in the cell transformation and tumour progression by stimulating cell growth, promoting tumour angiogenesis, mediating immune evasion and conferring resistance to apoptosis induced by chemotherapeutic agents (Niu et al, 2002;Real et al, 2002;Wei et al, 2003;Wang et al, 2004). However, whether Stat3 is activated in endometrial and cervical cancers is not known.…”

“…Stat3 has been classified as a protooncogene because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumour formation in nude mice (Bromberg et al, 1999;Bowman et al, 2000). Constitutive Stat3 signaling may participate in oncogenesis by stimulating cell proliferation, promoting angiogenesis, mediating immune evasion, and conferring resistance to apoptosis induced by conventional therapies (Niu et al, 2002;Real et al, 2002;Wei et al, 2003;Wang et al, 2004). Inhibition of constitutively active Stat3 can induce apoptosis and inhibit cancer cell growth (Buettner et al, 2002), indicating constitutive Stat3 signaling is required for cancer cell survival and growth.…”

Tumor stress, cell death and the ensuing immune response

“…86,87 In particular, signal transducer and activator of transcription 3 (STAT3) is frequently activated in cancers and mediates immune suppression by inhibiting the expression of proinflammatory chemokines and cytokines required for DC maturation. 88 In addition, STAT3 activation in tumor cells promotes STAT3 activation in DC and blunts their functions 89 as well as the migration of immune effectors into tumor beds. Independently, tumor cells could also express PD-L1/B7-H1, B7-H4 or IDO (indolamine 2,3-dioxygenase) which induce anergy or apoptosis of tumor-specific T cells.…”