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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer.

ABSTRACT: BACKGROUND:Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown. METHODS:We sought to quantify the effect of chemotherapy treatment on computationally predicted neoantigen expression for high grade serous ovarian carcinoma patients enrolled in the Australian Ovarian Cancer Study. In this series, 35 of 114 samples were collected after exposure to chemotherapy; 14 are matched with an untreated sample from the same patient. Our approach integrates whole genome and RNA sequencing of bulk tumor samples with class I MHC binding prediction and mutational signatures extracted from studies of chemotherapy-exposed Caenorhabditis elegans and Gallus gallus cells. We additionally investigated the relationship between neoantigens, tumor infiltrating immune cells estimated from RNA-seq with CIBERSORT, and patient survival. RESULTS:Greater neoantigen burden and CD8+ T cell infiltration in primary, pre-treatment samples were independently associated with improved survival. Relapse samples collected after chemotherapy harbored a median of 78% more expressed neoantigens than untreated primary samples, a figure that combines the effects of chemotherapy and other processes operative during relapse. The contribution from chemotherapy-associated signatures was small, accounting for a mean of 5% (range 0-16) of the expressed neoantigen burden in relapse samples. In both treated and untreated samples, most neoantigens were attributed to COSMIC Signature (3), associated with BRCA disruption, Signature (1), associated with a slow mutagenic process active in healthy tissue, and Signature (8), of unknown etiology. CONCLUSION:Relapsed ovarian cancers harbor more predicted neoantigens than primary tumors, but the increase is due to pre-existing mutational processes, not mutagenesis from chemotherapy.

SUBMITTER: O'Donnell T

PROVIDER: S-EPMC5778667 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer.

O'Donnell Timothy T Christie Elizabeth L EL Ahuja Arun A Buros Jacqueline J Aksoy B Arman BA Bowtell David D L DDL Snyder Alexandra A Hammerbacher Jeff J

BMC cancer 20180122 1

<h4>Background</h4>Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown.<h4>Methods</h4>We sought to quantify the effect of chemotherapy ...[more]

PMID: 29357823

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Project description:BackgroundEpithelial ovarian cancer accounts for about 90% of all cases of ovarian cancer. Debulking surgery and six courses of platinum-based chemotherapy results in complete clinical remission (CCR) in up to 75% of cases. However, 75% of the responders will relapse within a median time of 18 to 28 months and only 20% to 40% of women will survive beyond five years. It has been suggested that maintenance chemotherapy could assist in prolonging remission. To date, there has not been a systematic review on the impact of maintenance chemotherapy for epithelial ovarian cancer.ObjectivesTo assess the effectiveness and toxicity of maintenance chemotherapy for epithelial ovarian cancer and to evaluate the impact on quality of life (QoL).Search methodsIn the original review we searched the Cochrane Gynaecological Cancer Review Group Specialised Register, The Cochrane Central Register of Controlled Trails (CENTRAL, The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, PubMed, CBMdisc, CNKI and VIP (to May 2009). We collected information from ongoing trials, checked reference lists of published articles and consulted experts in the field. For this update, the searches were extended to October 2012.Selection criteriaRandomised controlled trials (RCTs) comparing maintenance chemotherapy with no further intervention, maintenance radiotherapy or other maintenance therapy.Data collection and analysisTwo review authors independently assessed trials for eligibility and quality and extracted data. We analysed overall survival (OS) and progression-free survival (PFS) rates as dichotomous variables. Toxicity and QoL data were extracted where present. All analyses were based on intention-to-treat (ITT) on the endpoint of survival. We also analysed data by subgroups of drugs.Main resultsWe included eight trials (1644 women). When all chemotherapy regimens were combined, meta-analysis indicated no significant difference in three-, five- and 10-year OS or PFS. For five-year OS, the combined risk ratio (RR) was 1.03 (95% confidence interval (CI) 0.96 to 1.10) and for the five-year PFS, the combined RR was 1.06 (95% CI 0.97 to 1.17). Results were very similar when trials of different regimens were analysed. Comparing chemotherapy with radiotherapy, only the RR for 10-year PFS in pathological complete remission (PCR) was in favour of whole abdominal radiotherapy 0.51 (95% CI 0.27 to 1.00), while three- and five-year OS rates have no significant difference between the two groups.Authors' conclusionsThere is no evidence to suggest that the use of platinum agents, doxorubicin or paclitaxel used as maintenance chemotherapy is more effective than observation alone. Further investigations regarding the effect of paclitaxel used as maintenance chemotherapy are required.

Project description:BACKGROUND:Efficient identification of neoantigen-specific T-cell responses in epithelial ovarian cancer (EOC) remains a challenge. Existing investigations of spontaneous T-cell response to tumor neoepitope in EOC have taken the approach of comprehensive screening all neoantigen candidates, with a validation rate of 0.5-2%. METHODS:Whole-exome and transcriptome sequencing analysis of treatment-naive EOC patients were performed to identify neoantigen candidates, and the immunogenicity of prioritized neoantigens was evaluated by analyzing spontaneous neoantigen-specfic CD4+ and CD8+ T-cell responses in the tumor and/or peripheral blood. The biological relevance of neoantigen-specific T-cell lines and clones were analyzed by evaluating the capacity of autologous ovarian tumor recognition. Genetic transfer of T-cell receptor (TCR) from these neoantigen-specific T-cell clones into peripheral blood T-cells was conducted to generate neoepitope-specific T-cells. The molecular signature associated with positive neoantigen T-cell responses was investigated, and the impacts of expression level and lymphocyte source on neoantigen identification were explored. RESULTS:Using a small subset of prioritized neoantigen candidates, we were able to detect spontaneous CD4+ and/or CD8+ T-cell responses against neoepitopes from autologous lymphocytes in half of treatment-naïve EOC patients, with a significantly improved validation rate of 19%. Tumors from patients exhibiting neoantigen-specific T-cell responses exhibited a signature of upregulated antigen processing and presentation machinery, which was also associated with favorable patient survival in the TCGA ovarian cohort. T-cells specific against two mutated cancer-associated genes, NUP214 and JAK1, recognized autologous tumors. Gene-engineering with TCR from these neoantigen-specific T-cell clones conferred neoantigen-reactivity to peripheral T-cells. CONCLUSIONS:Our study demonstrated the feasibility of efficiently identifying both CD4+ and CD8+ neoantigen-specific T-cells in EOC. Autologous lymphocytes genetically engineered with tumor antigen-specific TCR can be used to generate cells for use in the personalized adoptive T-cell transfer immunotherapy.

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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer.

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Chemotherapy weakly contributes to predicted neoantigen expression in ovarian cancer.

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