STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells

Abstract

STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice.

Improvement of immunogenic chemotherapy by STAT3 inhibition

“…Accordingly, neutralization of IFNAR or CXCR3 with suitable antibodies reversed the chemosensitivity of Stat3 ¡/¡ tumors in vivo. 10 This finding establishes the cause-effect relationship between STAT3 inhibition, stimulation of a type 1 interferon response and improved outcome of cancer chemotherapy.…”

“…10 Moreover, the frequency of g/d T cells, CD4 C a/b T cells and CD8 C a/b T cells among tumor-infiltrating leukocytes was only enhanced by the dual experimental manipulation (Stat3 knockout plus doxorubicin injection), which also caused an increase in capacity of tumor-infiltrating CD4…”

“…Moreover, retransfection of Stat3 ¡/¡ MCA205 cells with Stat3 (but not with a mutant, inactive form of Stat3) reversed their chemosensitivity. 10 Of note, after mitoxantrone treatment, Stat3 ¡/¡ MCA205 cancers induced a much stronger anticancer immune response than their WT counterparts. Thus, the chemotherapy-induced infiltration of the tumors by CD11c C…”

STAT3 inhibition for cancer therapy: Cell-autonomous effects only?

“…4,[10][11][12] Moreover, the inhibition of STAT3 allows malignant cells to secrete high amounts of Type I interferon and other products of so-called interferon response genes (IRGs), including chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10. 13,14 By virtue of this mechanism, STAT3 inhibition stimulates the recruitment of immune effectors into the tumor bed and improves immunosurveillance, especially in the context of ongoing anticancer immune responses. 13 Indeed, STAT3 inhibitors can be advantageously combined with immunogenic cell death (ICD)-inducing chemotherapeutic agents.…”

“…13 Indeed, STAT3 inhibitors can be advantageously combined with immunogenic cell death (ICD)-inducing chemotherapeutic agents. 13 Given the clinical impact of ICD inducers, [15][16][17][18][19][20][21][22] it will be important to explore this possibility in properly designed trials.…”