title: Rational Selection of Syngeneic Preclinical Tumor Models for Immunotherapeutic Drug Discovery.
abstract: Murine syngeneic tumor models are critical to novel immuno-based therapy development, but the molecular and immunologic features of these models are still not clearly defined. The translational relevance of differences between the models is not fully understood, impeding appropriate preclinical model selection for target validation, and ultimately hindering drug development. Across a panel of commonly used murine syngeneic tumor models, we showed variable responsiveness to immunotherapies. We used array comparative genomic hybridization, whole-exome sequencing, exon microarray analysis, and flow cytometry to extensively characterize these models, which revealed striking differences that may underlie these contrasting response profiles. We identified strong differential gene expression in immune-related pathways and changes in immune cell-specific genes that suggested differences in tumor immune infiltrates between models. Further investigation using flow cytometry showed differences in both the composition and magnitude of the tumor immune infiltrates, identifying models that harbor "inflamed" and "non-inflamed" tumor immune infiltrate phenotypes. We also found that immunosuppressive cell types predominated in syngeneic mouse tumor models that did not respond to immune-checkpoint blockade, whereas cytotoxic effector immune cells were enriched in responsive models. A cytotoxic cell-rich tumor immune infiltrate has been correlated with increased efficacy of immunotherapies in the clinic, and these differences could underlie the varying response profiles to immunotherapy between the syngeneic models. This characterization highlighted the importance of extensive profiling and will enable investigators to select appropriate models to interrogate the activity of immunotherapies as well as combinations with targeted therapies in vivo Cancer Immunol Res; 5(1); 29-41. ©2016 AACR.
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom. moselys@medimmune.com.
authors.forename: Suzanne I S
authors.initials: SI
authors.lastname: Mosely
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: John E
authors.initials: JE
authors.lastname: Prime
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Richard C A
authors.initials: RC
authors.lastname: Sainson
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Jens-Oliver
authors.initials: JO
authors.lastname: Koopmann
authors.affiliation: AstraZeneca Ltd, Cambridge, United Kingdom.
authors.forename: Dennis Y Q
authors.initials: DY
authors.lastname: Wang
authors.affiliation: AstraZeneca Ltd, Waltham, Massachusetts.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Greenawalt
authors.affiliation: AstraZeneca Ltd, Cambridge, United Kingdom.
authors.forename: Miika J
authors.initials: MJ
authors.lastname: Ahdesmaki
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Leyland
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mullins
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Luciano
authors.initials: L
authors.lastname: Pacelli
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Danielle
authors.initials: D
authors.lastname: Marcus
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Judith
authors.initials: J
authors.lastname: Anderton
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Watkins
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Jane
authors.initials: J
authors.lastname: Coates Ulrichsen
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland.
authors.forename: Philip
authors.initials: P
authors.lastname: Brohawn
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland.
authors.forename: Brandon W
authors.initials: BW
authors.lastname: Higgs
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: McCourt
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Hazel
authors.initials: H
authors.lastname: Jones
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: James A
authors.initials: JA
authors.lastname: Harper
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Morrow
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Viia
authors.initials: V
authors.lastname: Valge-Archer
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Stewart
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.affiliation: MedImmune Ltd, Cambridge, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing; D056747:Immunomodulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000074322:Antineoplastic Agents, Immunological; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen