title: Tumor-Infiltrating Plasma Cells Are Associated with Tertiary Lymphoid Structures, Cytolytic T-Cell Responses, and Superior Prognosis in Ovarian Cancer.
abstract: CD8(+) tumor-infiltrating lymphocytes (TIL) are key mediators of antitumor immunity and are strongly associated with survival in virtually all solid tumors. However, the prognostic effect of CD8(+) TIL is markedly higher in the presence of CD20(+) B cells, suggesting that cooperative interactions between these lymphocyte subsets lead to more potent antitumor immunity.
  
  
  
  We assessed the colocalization patterns, phenotypes, and gene expression profiles of tumor-associated T- and B-lineage cells in high-grade serous ovarian cancer (HGSC) by multicolor IHC, flow cytometry, and bioinformatic analysis of gene expression data from The Cancer Genome Atlas.
  
  
  
  T cells and B cells colocalized in four types of lymphoid aggregate, ranging from small, diffuse clusters to large, well-organized tertiary lymphoid structures (TLS) resembling activated lymph nodes. TLS were frequently surrounded by dense infiltrates of plasma cells (PC), which comprised up to 90% of tumor stroma. PCs expressed mature, oligoclonal IgG transcripts, indicative of antigen-specific responses. PCs were associated with the highest levels of CD8(+), CD4(+), and CD20(+) TIL, as well as numerous cytotoxicity-related gene products. CD8(+) TIL carried prognostic benefit only in the presence of PCs and these other TIL subsets. PCs were independent of mutation load, BRCA1/2 status, and differentiation antigens but positively associated with cancer-testis antigens.
  
  
  
  PCs are associated with the most robust, prognostically favorable CD8(+) TIL responses in HGSC. We propose that TLS facilitate coordinated antitumor responses involving the combined actions of cytolytic T cells and antibody-producing PCs. Clin Cancer Res; 22(12); 3005-15. ©2016 AACR.
authors.affiliation: Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Kroeger
authors.affiliation: Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada.
authors.forename: Katy
authors.initials: K
authors.lastname: Milne
authors.affiliation: 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 Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. bnelson@bccrc.ca.
authors.forename: Brad H
authors.initials: BH
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000912:Antibodies, Neoplasm / Q000276:immunology*; D053301:B-Cell Maturation Antigen / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology*; D011379:Prognosis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000072717:Tertiary Lymphoid Structures / Q000276:immunology*
chemical_list: D000912:Antibodies, Neoplasm; D053301:B-Cell Maturation Antigen; D007074:Immunoglobulin G; C086966:TNFRSF17 protein, human