Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes
- 14 October 2019
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 129 (11), 4992-5004
- https://doi.org/10.1172/jci127967
Abstract
Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify CD8(+) or CD4(+) lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer. We found that neoantigen-specific lymphocytes were preferentially enriched in the CD8(+)PD-1(+/hi) or CD4(+)PD-1(+/hi) subsets, but not in the corresponding bulk or PD-1(-) fractions. In 6 of 7 individuals analyzed we identified circulating CD8(+) and CD4(-) lymphocytes targeting 6 and 4 neoantigens, respectively. Moreover, neoantigen-reactive T cells and a T cell receptor (TCR) isolated from the CD8(+)PD-1(+) subsets recognized autologous tumor, albeit at reduced levels, in 2 patients with available cell lines. These data demonstrate the existence of circulating T cells targeting neoantigens in GI cancer patients and provide an approach to generate enriched populations of personalized neoantigen-specific lymphocytes and isolate TCRs that could be exploited therapeutically to treat cancer.Keywords
Funding Information
- Merck KGaA,Darmstadt, Germany (Grant for Oncology Innovation 2017)
This publication has 44 references indexed in Scilit:
- Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patientsNature Communications, 2019
- A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancerOncoImmunology, 2017
- Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patientsNature Medicine, 2016
- Immunogenicity of somatic mutations in human gastrointestinal cancersScience, 2015
- Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancerScience, 2015
- Genetic Basis for Clinical Response to CTLA-4 Blockade in MelanomaThe New England Journal of Medicine, 2014
- Mutational heterogeneity in cancer and the search for new cancer-associated genesNature, 2013
- Mutated PPP1R3B Is Recognized by T Cells Used To Treat a Melanoma Patient Who Experienced a Durable Complete Tumor RegressionThe Journal of Immunology, 2013
- Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T CellsImmunity, 2011
- Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiationNature Biotechnology, 2010