NK cells propagate T cell immunity following in situ tumor vaccination
Won Jong Jin,
Justin C. Jagodinsky,
Jessica M. Vera,
Paul A. Clark,
Cindy L. Zuleger,
Amy K. Erbe,
Irene M. Ong,
Trang Le,
Kaitlin Tetreault,
Tracy Berg,
Alexander L. Rakhmilevich,
KyungMann Kim,
Michael A. Newton,
Mark R. Albertini,
Paul M. Sondel,
Zachary S. Morris
Affiliations
Won Jong Jin
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Justin C. Jagodinsky
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Jessica M. Vera
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Paul A. Clark
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Cindy L. Zuleger
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Amy K. Erbe
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Irene M. Ong
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Trang Le
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Kaitlin Tetreault
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Tracy Berg
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Alexander L. Rakhmilevich
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
KyungMann Kim
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Michael A. Newton
Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Mark R. Albertini
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53792, USA; The Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, WI 53792, USA
Paul M. Sondel
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Zachary S. Morris
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA; Corresponding author
Summary: We report an in situ vaccination, adaptable to nearly any type of cancer, that combines radiotherapy targeting one tumor and intratumoral injection of this site with tumor-specific antibody and interleukin-2 (IL-2; 3xTx). In a phase I clinical trial, administration of 3xTx (with an immunocytokine fusion of tumor-specific antibody and IL-2, hu14.18-IL2) to subjects with metastatic melanoma increases peripheral CD8+ T cell effector polyfunctionality. This suggests the potential for 3xTx to promote antitumor immunity against metastatic tumors. In poorly immunogenic syngeneic murine melanoma or head and neck carcinoma models, 3xTx stimulates CD8+ T cell-mediated antitumor responses at targeted and non-targeted tumors. During 3xTx treatment, natural killer (NK) cells promote CTLA4+ regulatory T cell (Treg) apoptosis in non-targeted tumors. This is dependent on NK cell expression of CD86, which is upregulated downstream of KLRK1. NK cell depletion increases Treg infiltration, diminishing CD8+ T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8+ T cell immunity following 3xTx.
