Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation
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Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation. / Duraiswamy, Jaikumar; Turrini, Riccardo; Minasyan, Aspram; Barras, David; Crespo, Isaac; Grimm, Alizée J.; Casado, Julia; Genolet, Raphael; Benedetti, Fabrizio; Wicky, Alexandre; Ioannidou, Kalliopi; Castro, Wilson; Neal, Christopher; Moriot, Amandine; Renaud-Tissot, Stéphanie; Anstett, Victor; Fahr, Noémie; Tanyi, Janos L.; Eiva, Monika A.; Jacobson, Connor A.; Montone, Kathleen T.; Westergaard, Marie Christine Wulff; Svane, Inge Marie; Kandalaft, Lana E.; Delorenzi, Mauro; Sorger, Peter K.; Färkkilä, Anniina; Michielin, Olivier; Zoete, Vincent; Carmona, Santiago J.; Foukas, Periklis G.; Powell, Daniel J.; Rusakiewicz, Sylvie; Doucey, Marie Agnès; Dangaj Laniti, Denarda; Coukos, George.
I: Cancer Cell, Bind 39, Nr. 12, 2021, s. 1623-1642.e20.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation
AU - Duraiswamy, Jaikumar
AU - Turrini, Riccardo
AU - Minasyan, Aspram
AU - Barras, David
AU - Crespo, Isaac
AU - Grimm, Alizée J.
AU - Casado, Julia
AU - Genolet, Raphael
AU - Benedetti, Fabrizio
AU - Wicky, Alexandre
AU - Ioannidou, Kalliopi
AU - Castro, Wilson
AU - Neal, Christopher
AU - Moriot, Amandine
AU - Renaud-Tissot, Stéphanie
AU - Anstett, Victor
AU - Fahr, Noémie
AU - Tanyi, Janos L.
AU - Eiva, Monika A.
AU - Jacobson, Connor A.
AU - Montone, Kathleen T.
AU - Westergaard, Marie Christine Wulff
AU - Svane, Inge Marie
AU - Kandalaft, Lana E.
AU - Delorenzi, Mauro
AU - Sorger, Peter K.
AU - Färkkilä, Anniina
AU - Michielin, Olivier
AU - Zoete, Vincent
AU - Carmona, Santiago J.
AU - Foukas, Periklis G.
AU - Powell, Daniel J.
AU - Rusakiewicz, Sylvie
AU - Doucey, Marie Agnès
AU - Dangaj Laniti, Denarda
AU - Coukos, George
N1 - Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021
Y1 - 2021
N2 - The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.
AB - The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1+CD8+ TIL can be, however, polyfunctional. PD-1+ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.
KW - CD28
KW - CD40
KW - CTLA-4
KW - dendritic cell
KW - exhaustion
KW - myeloid niche
KW - ovarian
KW - PD-1
KW - TIL
KW - tumor
U2 - 10.1016/j.ccell.2021.10.008
DO - 10.1016/j.ccell.2021.10.008
M3 - Journal article
C2 - 34739845
AN - SCOPUS:85120666851
VL - 39
SP - 1623-1642.e20
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 12
ER -
ID: 302196217