title: Differentiated State of Initiating Tumor Cells Is Key to Distinctive Immune Responses Seen in H-RasG12V-Induced Squamous Tumors.
abstract: Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-RasG12Vis targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On aRag1-/-background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more tumors with shorter latency thanRag1+/+controls. Adoptive transfer and depletion studies revealed that B-cell and CD4 T-cell cooperation was critical for tumor yield, lymphocyte polarization, and tumor immune phenotype inRag1+/+mice of both models. Coculture of tumor-conditioned B cells with CD4 T cells implicated direct contact for Th1 and regulatory T cell (Treg) polarization, and CD40-CD40L for Th1, Th2, and Treg generation, a response not observed from splenic B cells. Anti-CD40L caused regression of InvRas tumors but enhanced growth in K14Ras, whereas a CD40 agonist mAb had opposite effects in each tumor model. These data show that position of tumor-initiating cells within a stratified squamous epithelial tissue provokes distinct B- and CD4 T-cell interactions, which establish unique tumor microenvironments that regulate tumor development and response to immunotherapy.Cancer Immunol Res; 5(3); 198-210. ©2017 AACR.
authors.affiliation: The Pennsylvania State University, The Huck Institutes of the Life Sciences, State College, Pennsylvania.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Podolsky
authors.affiliation: The Pennsylvania State University, The Huck Institutes of the Life Sciences, State College, Pennsylvania.
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Bailey
authors.affiliation: Earle A. Chiles Research Institute, Portland, Oregon.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gunderson
authors.affiliation: The Pennsylvania State University, The Huck Institutes of the Life Sciences, State College, Pennsylvania.
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Oakes
authors.affiliation: The Pennsylvania State University, The Huck Institutes of the Life Sciences, State College, Pennsylvania.
authors.forename: Kyle
authors.initials: K
authors.lastname: Breech
authors.affiliation: The Pennsylvania State University, The Huck Institutes of the Life Sciences, State College, Pennsylvania. Abg11@psu.edu.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication; D003062:Codon; D015870:Gene Expression; D011905:Genes, ras; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019013:CD40 Antigens; D003062:Codon; D023201:CD40 Ligand