title: Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients.
abstract: 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.
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alena
authors.identifier: http://orcid.org/0000-0002-1207-1880
authors.initials: A
authors.lastname: Gros
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Parkhurst
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Tran
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Pasetto
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Sadia
authors.initials: S
authors.lastname: Ilyas
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Gartner
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Crystal
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ilana M
authors.initials: IM
authors.lastname: Roberts
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Kasia
authors.initials: K
authors.lastname: Trebska-McGowan
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Surgery Branch, National Cancer Institute (NCI), National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000097:blood / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000097:blood / Q000235:genetics* / Q000276:immunology; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell