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

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

Cancer cell (2021-11-06)

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 Jacobson, Kathleen 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

PMID34739845

RESUMEN

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.