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Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients
Open accessAbstract
Detection of lymphocytes that target tumor-specific mutant neoantigens—derived from products encoded by mutated genes in the tumor—is mostly limited to tumor-resident lymphocytes, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8+ lymphocytes that reside in the tumor. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8+PD-1+, but not CD8+PD-1−, cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8+PD-1+ cells appeared similar, implying that the circulating CD8+PD-1+ lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.
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Metadata
- Authors
- Gros, A., Parkhurst, M. R., Tran, E., Pasetto, A., Robbins, P. F., Ilyas, S., Prickett, T. D., Gartner, J. J., Crystal, J. S., Roberts, I. M., Trebska-McGowan, K., Wunderlich, J. R., Yang, J. C., & Rosenberg, S. A.
- Venue
- Nature Medicine
- Published
- 2016-02-22
- Volume
- 22
- Issue
- 4
- Pages
- 433-438
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2282550179
- Cited by
- 829
- References
- 14
- FWCI
- 54.39
- Type
- journal article
- Language
- en
- Open access
- green
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