T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors

Cancer Res. 2017 Feb 1;77(3):658-671. doi: 10.1158/0008-5472.CAN-16-0725. Epub 2016 Nov 21.


Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene-engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFα derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. Cancer Res; 77(3); 658-71. ©2016 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology*
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / transplantation*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Immunohistochemistry
  • Immunotherapy, Adoptive / methods*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Minor Histocompatibility Antigens / immunology*
  • Prostatic Neoplasms / pathology*
  • Real-Time Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / biosynthesis*


  • Minor Histocompatibility Antigens
  • Tumor Necrosis Factor-alpha