title: PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.
abstract: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8⁺ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8⁺ TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8⁺ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8⁺ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8⁺ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8⁺PD-1⁺ compared with CD8⁺PD-1- TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8⁺ and the CD8⁺PD-1⁺ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.
authors.forename: Alena
authors.initials: A
authors.lastname: Gros
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.forename: Xin
authors.initials: X
authors.lastname: Yao
authors.forename: Yong F
authors.initials: YF
authors.lastname: Li
authors.forename: Simon
authors.initials: S
authors.lastname: Turcotte
authors.forename: Eric
authors.initials: E
authors.lastname: Tran
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.forename: Arnold
authors.initials: A
authors.lastname: Mixon
authors.forename: Shawn
authors.initials: S
authors.lastname: Farid
authors.forename: Mark E
authors.initials: ME
authors.lastname: Dudley
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hanada
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Almeida
authors.forename: Sam
authors.initials: S
authors.lastname: Darko
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: James C
authors.initials: JC
authors.lastname: Yang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D019264:Adoptive Transfer; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human