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

Research output: Contribution to journalArticle

97 Citations (Scopus)

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
StatePublished - Feb 21 2013

Fingerprint

Follicular Lymphoma
T-cells
Tumors
Cytokines
T-Lymphocytes
Neoplasms
Programmed Cell Death 1 Receptor
Blood
Phosphorylation
Histiocytes
Flow cytometry
Palatine Tonsil
Cell culture
Interleukin-4
Interleukin-10
Non-Hodgkin's Lymphoma
Immunotherapy
Blood Cells
Flow Cytometry

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

High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. / Myklebust, June H.; Irish, Jonathan M.; Brody, Joshua; Czerwinski, Debra K.; Houot, Roch; Kohrt, Holbrook E.; Timmerman, John; Said, Jonathan; Green, Michael R.; Delabie, Jan; Kolstad, Arne; Alizadeh, Ash A.; Levy, Ronald.

In: Blood, Vol. 121, No. 8, 21.02.2013, p. 1367-1376.

Research output: Contribution to journalArticle

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 2013, 'High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells', Blood, vol. 121, no. 8, pp. 1367-1376. https://doi.org/10.1182/blood-2012-04-421826
Myklebust, June H. ; Irish, Jonathan M. ; Brody, Joshua ; Czerwinski, Debra K. ; Houot, Roch ; Kohrt, Holbrook E. ; Timmerman, John ; Said, Jonathan ; Green, Michael R. ; Delabie, Jan ; Kolstad, Arne ; Alizadeh, Ash A. ; Levy, Ronald. / High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. In: Blood. 2013 ; Vol. 121, No. 8. pp. 1367-1376.
@article{aee25943a7024a65818ff58657617d15,
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-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.",
author = "Myklebust, {June H.} and Irish, {Jonathan M.} and Joshua Brody and Czerwinski, {Debra K.} and Roch Houot and Kohrt, {Holbrook E.} and John Timmerman and Jonathan Said and Green, {Michael R.} and Jan Delabie and Arne Kolstad and Alizadeh, {Ash A.} and Ronald Levy",
year = "2013",
month = "2",
day = "21",
doi = "10.1182/blood-2012-04-421826",
language = "English (US)",
volume = "121",
pages = "1367--1376",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84874442281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84874442281&partnerID=8YFLogxK

U2 - 10.1182/blood-2012-04-421826

DO - 10.1182/blood-2012-04-421826

M3 - Article

C2 - 23297127

AN - SCOPUS:84874442281

VL - 121

SP - 1367

EP - 1376

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -