Jin et al. found that radiation combined with injection of IL-2 and a tumor-specific antibody, all to the same tumor site, induced tumor-specific T cell responses and enhanced the infiltration of T cells and NK cells in non-targeted tumors. The inhibitory effect of Tregs at distant tumor sites was overcome by KLRK1-dependent upregulation of CD86 on NK cells, and the direct killing of CTLA-4+ Tregs by CD86+ NK cells, improving tumor regression and survival in poorly immunogenic murine tumor models. In two patients with metastatic melanoma, targeted radiation plus intratumoral injection of a tumor-specific antibody (anti-GD2) fused to IL-2 increased circulating polyfunctional CD8+ T cells.
Contributed by Ute Burkhardt
ABSTRACT: 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 (T(reg)) apoptosis in non-targeted tumors. This is dependent on NK cell expression of CD86, which is upregulated downstream of KLRK1. NK cell depletion increases T(reg) infiltration, diminishing CD8(+) T cell-dependent antitumor response. These findings demonstrate that NK cells sustain and propagate CD8(+) T cell immunity following 3xTx.
Author Info: (1) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (2) Department of Human Oncology, University of Wisconsin Sc
Author Info: (1) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (2) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (3) Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (4) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (5) Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (6) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (7) Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (8) Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (9) Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (10) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (11) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (12) Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (13) Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. (14) 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. (15) 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. (16) Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. Electronic address: zmorris@humonc.wisc.edu.
