TY - JOUR
T1 - High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells
AU - Myklebust, June H.
AU - Irish, Jonathan M.
AU - Brody, Joshua
AU - Czerwinski, Debra K.
AU - Houot, Roch
AU - Kohrt, Holbrook E.
AU - Timmerman, John
AU - Said, Jonathan
AU - Green, Michael R.
AU - Delabie, Jan
AU - Kolstad, Arne
AU - Alizadeh, Ash A.
AU - Levy, Ronald
PY - 2013/2/21
Y1 - 2013/2/21
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2012-04-421826
DO - 10.1182/blood-2012-04-421826
M3 - Article
C2 - 23297127
AN - SCOPUS:84874442281
SN - 0006-4971
VL - 121
SP - 1367
EP - 1376
JO - Blood
JF - Blood
IS - 8
ER -