Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation

Jaikumar Duraiswamy, Riccardo Turrini, Aspram Minasyan, David Barras, Isaac Crespo, Alizée J. Grimm, Julia Casado, Raphael Genolet, Fabrizio Benedetti, Alexandre Wicky, Kalliopi Ioannidou, Wilson Castro, Christopher Neal, Amandine Moriot, Stéphanie Renaud-Tissot, Victor Anstett, Noémie Fahr, Janos L. Tanyi, Monika A. Eiva, Connor A. JacobsonKathleen T. Montone, Marie Christine Wulff Westergaard, Inge Marie Svane, Lana E. Kandalaft, Mauro Delorenzi, Peter K. Sorger, Anniina Färkkilä, Olivier Michielin, Vincent Zoete, Santiago J. Carmona, Periklis G. Foukas, Daniel J. Powell, Sylvie Rusakiewicz, Marie Agnès Doucey, Denarda Dangaj Laniti, George Coukos*

*Corresponding author for this work
39 Citations (Scopus)


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.

Original languageEnglish
JournalCancer Cell
Issue number12
Pages (from-to)1623-1642.e20
Publication statusPublished - 13 Dec 2021


  • CD28
  • CD40
  • CTLA-4
  • dendritic cell
  • exhaustion
  • myeloid niche
  • ovarian
  • PD-1
  • TIL
  • tumor


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