Chimeric PD-1:28 receptor upgrades low-avidity T cells and restores effector function of tumor-infiltrating lymphocytes for adoptive cell therapy


  • R. Schlenker
  • L.F. Olguín-Contreras
  • M. Leisegang
  • J. Schnappinger
  • A. Disovic
  • S. Rühland
  • P.J. Nelson
  • H. Leonhardt
  • H. Harz
  • S. Wilde
  • D.J. Schendel
  • W. Uckert
  • G. Willimsky
  • E. Noessner


  • Cancer Research


  • Canc Res 77 (13): 3577-3590


  • Inherent intermediate-to-low affinity T cell receptors (TCR) that develop during the natural course of immune responses may not allow sufficient activation for tumor elimination, making the majority of T cells suboptimal for adoptive T cell therapy (ATT). TCR affinity enhancement has been implemented to provide stronger T cell activity but carries the risk of creating undesired cross-reactivity leading to potential serious adverse effects in clinical application. We demonstrate here that engineering of low-avidity T cells recognizing a naturally processed and presented tumor-associated antigen with a chimeric PD-1:28 receptor increases effector function to levels seen with high-avidity T cells of identical specificity. Upgrading the function of low-avidity T cells without changing the TCR affinity will allow a large arsenal of low-avidity T cells previously thought to be therapeutically inefficient to be considered for ATT. PD-1:28 engineering re-instated Th1 function in tumor-infiltrating lymphocytes (TILs) that had been functionally disabled in the human renal cell carcinoma (RCC) environment without unleashing undesired Th2 cytokines or IL-10. Involved mechanisms may be correlated to restoration of ERK and AKT signaling pathways. In mouse tumor models of ATT, PD-1:28 engineering enabled low-avidity T cells to proliferate stronger and prevented PD-L1 upregulation and Th2 polarization in the tumor milieu. Engineered T cells combined with checkpoint blockade secreted significantly more IFN-{gamma} compared to T cells without PD-1:28, suggesting a beneficial combination with checkpoint blockade therapy or other therapeutic strategies. Altogether, the supportive effects of PD-1:28 engineering on T cell function makes it an attractive tool for ATT.