Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells

Nat Immunol. 2023 May;24(5):869-883. doi: 10.1038/s41590-023-01477-2. Epub 2023 Apr 20.


To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2Rβγ receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led-in the absence of lymphodepletion or exogenous cytokine support-to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes* / immunology
  • Cell Line, Tumor
  • Female
  • Immunotherapy, Adoptive*
  • Interleukin-2* / pharmacology
  • Interleukin-33
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental* / therapy
  • Programmed Cell Death 1 Receptor / metabolism
  • Protein Engineering
  • T-Cell Exhaustion


  • Interleukin-2
  • Interleukin-33
  • Programmed Cell Death 1 Receptor