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

Myklebust JH, Irish JM, Brody J, Czerwinski DK, Houot R, Kohrt HE, Timmerman J, Said J, Green MR, Delabie J, Kolstad A, Alizadeh AA, Levy R
Blood. 2013 121 (8): 1367-76

PMID: 23297127 · PMCID: PMC3578953 · DOI:10.1182/blood-2012-04-421826

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.

MeSH Terms (18)

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

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