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: 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
• Journal: Blood (Blood) Vol. 121 Issue 8 Pg. 1367-76 (Feb 21 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23297127 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• E-Selectin
• IL10 protein, human
• IL4 protein, human
• Interleukins
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Interleukin-10
• Interleukin-4
• Leukocyte Common Antigens
• PTPRC protein, human
• interleukin-21

Topics

• CD4-Positive T-Lymphocytes (cytology, immunology, metabolism)
• Cell Separation (methods)
• Cells, Cultured
• Child
• Cytokines (metabolism)
• E-Selectin (metabolism)
• Flow Cytometry (methods)
• Histiocytes (metabolism, pathology)
• Humans
• Interleukin-10 (metabolism)
• Interleukin-4 (metabolism)
• Interleukins (metabolism)
• Leukocyte Common Antigens (metabolism)
• Lymphoma, Follicular (immunology, metabolism, pathology)
• Palatine Tonsil (cytology, immunology)
• Programmed Cell Death 1 Receptor (immunology, metabolism)
• Signal Transduction (immunology)
• Tumor Microenvironment (immunology)