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

Cancer Cell. 2021 Dec 13;39(12):1623-1642.e20. doi: 10.1016/j.ccell.2021.10.008. Epub 2021 Nov 4.


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.

Keywords: CD28; CD40; CTLA-4; PD-1; TIL; dendritic cell; exhaustion; myeloid niche; ovarian; tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Presenting Cells / metabolism*
  • CD28 Antigens / metabolism*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Myeloid Cells / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Stem Cell Niche / genetics*


  • CD28 Antigens
  • Immune Checkpoint Inhibitors