title: IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors.
abstract: Many signal transduction inhibitors are being developed for cancer therapy target pathways that are also important for the proper function of antitumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T-cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor rechallenge. Our work identifies a clinically actionable approach to overcome the T-cell-suppressive effects of MEK inhibitors and illustrates how to reconcile the deficiencies of signal transduction inhibitors, which impede desired immunologic effects in vivo Cancer Res; 76(9); 2561-72. ©2016 AACR.
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Svoronos
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tesone
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Fahmida
authors.initials: F
authors.lastname: Sarmin
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Mee R
authors.initials: MR
authors.lastname: Sheen
authors.affiliation: Research & Development, Altor BioScience Corporation, Miramar, Florida.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Jeng
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania. Rena Rowan Breast Center, University of Pennsylvania, Philadelphia, Pennsylvania. Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.affiliation: Research & Development, Altor BioScience Corporation, Miramar, Florida.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: Tumor Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania. jrconejo@wistar.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006801:Humans; D019409:Interleukin-15; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C582303:ALT-803; D019409:Interleukin-15; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011728:Pyridones; D011744:Pyrimidinones; D011993:Recombinant Fusion Proteins; C560077:trametinib