Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 3,87 MB, PDF-dokument
Background Cancer is characterized by an accumulation of somatic mutations, of which a significant subset can generate cancer-specific neoepitopes that are recognized by autologous T cells. Such neoepitopes are emerging as important targets for cancer immunotherapy, including personalized cancer vaccination strategies. Methods We used whole-exome and RNA sequencing analysis to identify potential neoantigens for a patient with non-small cell lung cancer. Thereafter, we assessed the autologous T-cell reactivity to the candidate neoantigens using a long peptide approach in a cultured interferon gamma ELISpot and tracked the neoantigen-specific T-cells in the tumor by T-cell receptor (TCR) sequencing. In parallel, identified gene variants were incorporated into a Modified Vaccinia Ankara-based vaccine, which was evaluated in the human leucocyte antigen A∗0201 transgenic mouse model (HHD). Results Sequencing revealed a tumor with a low mutational burden: 2219 sequence variants were identified from the primary tumor, of which 23 were expressed in the transcriptome, involving 18 gene products. We could demonstrate spontaneous T-cell responses to 5/18 (28%) mutated gene variants, and further analysis of the TCR repertoire of neoantigen-specific CD4 + and CD8 + T cells revealed TCR clonotypes that were expanded in both blood and tumor tissue. Following vaccination of HHD mice, de novo T-cell responses were generated to 4/18 (22%) mutated gene variants; T cells reactive against two variants were also evident in the autologous setting. Subsequently, we determined the major histocompatibility complex restriction of the T-cell responses and used in silico prediction tools to determine the likely neoepitopes. Conclusions Our study demonstrates the feasibility of efficiently identifying tumor-specific neoantigens that can be targeted by vaccination in tumors with a low mutational burden, promising successful clinical exploitation, with trials currently underway.
Originalsprog | Engelsk |
---|---|
Artikelnummer | e003821 |
Tidsskrift | Journal for ImmunoTherapy of Cancer |
Vol/bind | 10 |
Udgave nummer | 3 |
Antal sider | 14 |
ISSN | 2051-1426 |
DOI | |
Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Contributors KM: study conception, experimental work, data interpretation, paper writing, paper review; AvW: experimental work, data interpretation, paper writing, paper review; JT: bioinformatic evaluation, data interpretation, paper writing, paper review; CW: animal experimental work, data interpretation, paper writing, paper review; OW: experimental work, data interpretation, paper writing, paper review; DS: experimental work, data interpretation, paper review; KBo: experimental work, data interpretation, paper review; KBe: conception of the experimental works, paper review; NSi: vaccine design, paper review; FCN: experimental work, paper review; GT: data interpretation, paper review; TS-E: data interpretation, paper review; JG: bioinformatic evaluation, data interpretation, paper review; SS: data interpretation, paper review; BP: data interpretation, paper review; PV: data interpretation, paper review; NSa: supervised animal work, data interpretation, paper writing, paper review; CHO: conceived, supervised and led the work, data interpretation, paper writing, paper review.Author acting as guarantor, CHO Funding This study was supported by a Cancer Research UK Centres Network Accelerator Award Grant (A21998). CHO is supported by I-CURE. AvW was supported by DFG fellowship (Deutsche Forschungsgemeinschaft, DFG; research fellowship # WI 5255/1-1:1).
Publisher Copyright:
©
ID: 321195795