High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells

June H. Myklebust, Jonathan M. Irish, Joshua Brody, Debra K. Czerwinski, Roch Houot, Holbrook E. Kohrt, John Timmerman, Jonathan Said, Michael R. Green, Jan Delabie, Arne Kolstad, Ash A. Alizadeh, Ronald Levy

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97 Scopus citations

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-1hi FL TILs, containing TFH 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-1hi subset. Because FLTILs 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.

Original languageEnglish (US)
Pages (from-to)1367-1376
Number of pages10
JournalBlood
Volume121
Issue number8
DOIs
Publication statusPublished - Feb 21 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Myklebust, J. H., Irish, J. M., Brody, J., Czerwinski, D. K., Houot, R., Kohrt, H. E., ... Levy, R. (2013). High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood, 121(8), 1367-1376. https://doi.org/10.1182/blood-2012-04-421826