Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients

Steven Rosenberg and colleagues report that PD-1 is a biomarker of CD8 + T cells in the blood that recognize mutated neoantigens in melanoma. 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 1 , 2 , 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 3 . 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.