title: STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade.
abstract: In preclinical tumor models, αOX40 therapy is often successful at treating small tumors, but is less effective once the tumors become large. For a tumor immunotherapy to be successful to cure large tumors, it will most likely require not only an agonist to boost effector T-cell function but also inhibitors of T-cell suppression. In this study, we show that combining αOX40 antibodies with an inhibitor of the TGFβ receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT26 tumors. Evaluation of tumor-infiltrating T cells showed that SM16/αOX40 dual therapy resulted in an increase in proliferating granzyme B(+) CD8 T cells, which produced higher levels of IFNγ, compared with treatment with either agent alone. We also found that the dual treatment increased pSTAT3 expression in both CD4 and CD8 T cells isolated from tumors. Because others have published that STAT3 signaling is detrimental to T-cell function within the tumor microenvironment, we explored whether deletion of STAT3 in OX40-expressing cells would affect this potent combination therapy. Surprisingly, we found that deletion of STAT3 in OX40-expressing cells decreased the efficacy of this combination therapy, showing that the full therapeutic potential of this treatment depends on STAT3 signaling, most likely in the T cells of tumor-bearing mice.
authors: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon.
authors: Todd A
authors: TA
authors: Triplett
authors: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors: Christopher G
authors: CG
authors: Tucker
authors: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors: Kendra C
authors: KC
authors: Triplett
authors: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.
authors: Zefora
authors: Z
authors: Alderman
authors: Oncology Cell Signaling, Biogen Idec, Cambridge, Massachusetts.
authors: Lihong
authors: L
authors: Sun
authors: Oncology Cell Signaling, Biogen Idec, Cambridge, Massachusetts.
authors: Leona E
authors: LE
authors: Ling
authors: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon. andrew.weinberg@providence.org eakporiaye@sidra.org.
authors: Emmanuel T
authors: ET
authors: Akporiaye
authors: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon. andrew.weinberg@providence.org eakporiaye@sidra.org.
authors: Andrew D
authors: AD
authors: Weinberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D053961:Azabicyclo Compounds / Q000008:administration & dosage; D045744:Cell Line, Tumor; D005260:Female; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors* / Q000276:immunology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D053961:Azabicyclo Compounds; D053262:Receptors, OX40; D018125:Receptors, Transforming Growth Factor beta; C528106:SM16 compound; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse