Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer.

Content Provider	Semantic Scholar
Author	Wick, Darin A. Webb, John R. Nielsen, Julie Søgaard Martin, Spencer David Kroeger, David R. Milne, Katy Castellarin, Mauro Twumasi-Boateng, Kwame Watson, Peter Hamilton Holt, Rob A. Nelson, Brad H.
Copyright Year	2014
Abstract	PURPOSE 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. EXPERIMENTAL DESIGN 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. CONCLUSION 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.
Starting Page	269
Ending Page	270
Page Count	2
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/early/2013/12/07/1078-0432.CCR-13-2147.full.pdf
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/20/5/1125.full.pdf
PubMed reference number	24323902v1
Alternate Webpage(s)	https://doi.org/10.1158/1078-0432.CCR-13-2147
DOI	10.1158/1078-0432.ccr-13-2147
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume Number	20
Issue Number	5
Language	English
Access Restriction	Open
Subject Keyword	Biomarkers, Tumor Chronic Lymphocytic Leukemia Disease Progression Enzyme-Linked Immunospot Assay Hydroxysteroid Dehydrogenases Hydroxysteroids Immune system Leukemia, B-Cell Malignant neoplasm of ovary Mutation Neoplasms Patients T-Lymphocyte Tumor Immunity Whole Exome Sequencing ovarian neoplasm primary tumor recurrent ovarian epithelial cancer
Content Type	Text
Resource Type	Article