PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors

摘要: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression metastatic melanoma; however, TILs are a heterogeneous population, and there no effective markers to specifically identify select the repertoire tumor-reactive mutation-specific CD8+ lymphocytes. The lack biomarkers limits ability study these cells develop strategies enhance clinical efficacy extend this therapy other malignancies. Here, we evaluated unique phenotypic traits TCR β chain (TCRβ) clonotypic frequency in melanoma tumors patient-specific repertoires In all 6 studied, expression inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; CD223), T immunoglobulin mucin domain (TIM-3) on identified autologous repertoire, including mutated neoantigen-specific lymphocytes, whereas only fraction population expressed costimulatory receptor 4-1BB (also CD137). TCRβ deep sequencing revealed oligoclonal expansion specific clonotypes CD8+PD-1+ compared with CD8+PD-1– TIL populations. Furthermore, most highly expanded populations recognized tumor included targeting antigens. Thus, addition well-documented negative regulatory role PD-1 cells, our findings demonstrate that accurately identifies clonally reveal dual importance microenvironment.