| Literature DB >> 34739845 |
Jaikumar Duraiswamy1, Riccardo Turrini2, Aspram Minasyan2, David Barras3, Isaac Crespo2, Alizée J Grimm2, Julia Casado4, Raphael Genolet2, Fabrizio Benedetti2, Alexandre Wicky5, Kalliopi Ioannidou2, Wilson Castro2, Christopher Neal2, Amandine Moriot2, Stéphanie Renaud-Tissot6, Victor Anstett2, Noémie Fahr2, Janos L Tanyi1, Monika A Eiva7, Connor A Jacobson8, Kathleen T Montone9, Marie Christine Wulff Westergaard10, Inge Marie Svane10, Lana E Kandalaft6, Mauro Delorenzi11, Peter K Sorger8, Anniina Färkkilä12, Olivier Michielin5, Vincent Zoete2, Santiago J Carmona2, Periklis G Foukas13, Daniel J Powell7, Sylvie Rusakiewicz6, Marie-Agnès Doucey2, Denarda Dangaj Laniti2, George Coukos14.
Abstract
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.Entities:
Keywords: CD28; CD40; CTLA-4; PD-1; TIL; dendritic cell; exhaustion; myeloid niche; ovarian; tumor
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Year: 2021 PMID： 34739845 PMCID： PMC8861565 DOI： 10.1016/j.ccell.2021.10.008
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743