title: High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells.
abstract: Defects in T-cell function in patients with cancer might influence their capacity to mount efficient antitumor immune responses. Here, we identified highly reduced IL-4-, IL-10-, and IL-21-induced phosphorylation of STAT6 and STAT3 in tumor-infiltrating T cells (TILs) in follicular lymphoma (FL) tumors, contrasting other non-Hodgkin lymphoma TILs. By combining phospho-protein-specific flow cytometry with several T-cell markers, we identified that CD4(+)CD45RO(+)CD62L(-) FL TILs were largely nonresponsive to cytokines, in contrast to the corresponding autologous peripheral blood subset. We observed differential expression of the inhibitory receptor PD-1 in FL TILs and peripheral blood T cells. Furthermore, CD4(+)PD-1(hi) FL TILs, containing T(FH) and non-T(FH) cells, had lost their cytokine responsiveness, whereas PD-1 TILs had normal cytokine signaling. However, this phenomenon was not tumor specific, because tonsil T cells were similar to FL TILs. FL tumor cells were negative for PD-1 ligands, but PD-L1(+) histiocytes were found within the T cell-rich zone of the neoplastic follicles. Disruption of the microenvironment and in vitro culture of FL TILs could restore cytokine signaling in the PD-1(hi) subset. Because FL TILs in vivo probably receive suppressive signals through PD-1, this provides a rationale for testing PD-1 Ab in combination with immunotherapy in patients with FL.
authors.affiliation: Department of Medicine, Oncology Division, Stanford University, Stanford, CA, USA.
authors.forename: June H
authors.initials: JH
authors.lastname: Myklebust
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Irish
authors.forename: Joshua
authors.initials: J
authors.lastname: Brody
authors.forename: Debra K
authors.initials: DK
authors.lastname: Czerwinski
authors.forename: Roch
authors.initials: R
authors.lastname: Houot
authors.forename: Holbrook E
authors.initials: HE
authors.lastname: Kohrt
authors.forename: John
authors.initials: J
authors.lastname: Timmerman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Said
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.forename: Arne
authors.initials: A
authors.lastname: Kolstad
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D006644:Histiocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008224:Lymphoma, Follicular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D019040:E-Selectin; C508609:IL10 protein, human; C508598:IL4 protein, human; D007378:Interleukins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human; D000098546:Interleukin-21