A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients.
Overcoming the profound immunosuppression in patients with solid cancers has impeded efficacious immunotherapy. Signal transducers and activators of transcription 3 (STAT3) has recently emerged as a potential target for effective immunotherapy, and in this study, we describe a novel small molecule inhibitor of STAT3 that can penetrate the central nervous system (CNS) in mice and in physiologically relevant doses in vitro and reverse tolerance in immune cells isolated from glioblastoma multiforme (GBM) patients. Specifically, it induces the expression of costimulatory molecules on peripheral macrophages and tumor-infiltrating microglia, stimulates the production of the immune-stimulatory cytokines interleukin 2 (IL-2), IL-4, IL-12, and IL-15, and induces proliferation of effector T cells from GBM patients that are refractory to CD3 stimulation. We show that the functional enhancement of immune responses after STAT3 inhibition is accompanied by up-regulation of several key intracellular signaling molecules that critically regulate T-cell and monocyte activation. Specifically, the phosphorylation of Syk (Tyr352) in monocytes and ZAP-70 (Tyr319) in T cells are enhanced by the STAT-3 inhibitor in marked contrast to toll-like receptor and T-cell receptor agonists, respectively. This novel small molecule STAT3 inhibitor has tremendous potential for clinical applications with its penetration into the CNS, easy parental administration, direct tumor cytotoxicity, and potent immune adjuvant responses in immunosuppressed cancer patients.
Hussain
S Farzana
SF
Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kong
Ling-Yuan
LY
Jordan
Justin
J
Conrad
Charles
C
Madden
Timothy
T
Fokt
Isabella
I
Priebe
Waldemar
W
Heimberger
Amy B
AB
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000276:immunology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D011725:Pyridines / Q000276:immunology / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D020032:Tyrphostins / Q000276:immunology / Q000494:pharmacology*; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D020032:Tyrphostins; C519885:WP1066; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase