title: Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer.
abstract: OBJECTIVE
  Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer undergoing standard treatment.
  
  
  METHODS
  Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence.
  
  
  RESULTS
  The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specific CD8(+) T-cell response to the mutation hydroxysteroid dehydrogenase-like protein 1 (HSDL1)(L25V) was detected in one patient. In the primary tumor, the HSDL1(L25V) mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1(L25V)-specific CD8(+) T-cell response. At second recurrence, the HSDL1(L25V) mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable.
  
  
  CONCLUSIONS
  The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, was transient, and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy.
authors: Authors' Affiliations: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency; Department of Biochemistry and Microbiology, University of Victoria, Victoria; Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver; Departments of Medical Genetics and Pathology and Laboratory Medicine, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors: Darin A
authors: DA
authors: Wick
authors: John R
authors: JR
authors: Webb
authors: Julie S
authors: JS
authors: Nielsen
authors: Spencer D
authors: SD
authors: Martin
authors: David R
authors: DR
authors: Kroeger
authors: Katy
authors: K
authors: Milne
authors: Mauro
authors: M
authors: Castellarin
authors: Kwame
authors: K
authors: Twumasi-Boateng
authors: Peter H
authors: PH
authors: Watson
authors: Rob A
authors: RA
authors: Holt
authors: Brad H
authors: BH
authors: Nelson
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D007150:Immunohistochemistry; D007157:Immunologic Surveillance; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D009154:Mutation; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; C464422:HSDL1 protein, human; D006913:Hydroxysteroid Dehydrogenases