title: Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade serous ovarian carcinoma.
abstract: BACKGROUND
  When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL) could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer.
  
  
  RESULTS
  In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3)) and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1)) correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049-5.106); p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF) expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097-5.799); p = 0.0294].
  
  
  CONCLUSIONS
  Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Katelin N
authors.initials: KN
authors.lastname: Townsend
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Jaeline E
authors.initials: JE
authors.lastname: Spowart
authors.affiliation: Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
authors.forename: Hassan
authors.initials: H
authors.lastname: Huwait
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sima
authors.initials: S
authors.lastname: Eshragh
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: West
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Elrick
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Kalloger
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Anglesio
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada ; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Watson
authors.affiliation: Centre for the Translational & Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada ; Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada ; Department of Biology, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Lum
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001343:Autophagy; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D015687:Cell Hypoxia; D018284:Cystadenocarcinoma, Serous / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D016019:Survival Analysis; D000074019:T-Cell Intracellular Antigen-1; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D039102:Poly(A)-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D053804:Granzymes