Prospective identification of neoantigen specific lymphocytes in the peripheral blood of melanoma patients
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.
Nature Medicine