title: PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer.
abstract: OBJECTIVE
  We have previously demonstrated that patients with metastatic colorectal cancer who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared with patients in whom responses do not occur. We sought to characterize the patterns of T-lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine.
  
  
  METHODS
  Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 nonresponders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the combined multivariate and collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane-related functions.
  
  
  RESULTS
  There was no correlation between vaccine response and intratumor, peritumor, or hepatic densities of T-cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%).
  
  
  CONCLUSIONS
  Adjuvant DC vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins. Clin Cancer Res; 23(2); 399-406. ©2016 AACR.
authors.affiliation: Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire.
authors.forename: David C
authors.initials: DC
authors.lastname: Qian
authors.affiliation: Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Arief A
authors.initials: AA
authors.lastname: Suriawinata
authors.affiliation: Department of Computer Science, Dartmouth College, Hanover, New Hampshire.
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Her
authors.affiliation: Department of Biomedical Data Science, Dartmouth Geisel School of Medicine, Lebanon, New Hampshire. Richard.J.Barth.Jr@hitchcock.org Christopher.I.Amos@dartmouth.edu.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.affiliation: Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Richard.J.Barth.Jr@hitchcock.org Christopher.I.Amos@dartmouth.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barth
mesh_terms: D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D015179:Colorectal Neoplasms / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008565:Membrane Proteins / Q000097:blood*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D019496:Cancer Vaccines; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human