Abstract
Inefficient T cell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS⁺ M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
CD4-Positive T-Lymphocytes / immunology*
-
CD4-Positive T-Lymphocytes / transplantation
-
CD8-Positive T-Lymphocytes / immunology*
-
CD8-Positive T-Lymphocytes / transplantation
-
Cell Differentiation / radiation effects
-
Cells, Cultured
-
Female
-
Humans
-
Immunotherapy, Adoptive
-
Inflammation Mediators / metabolism
-
Insulinoma / blood supply
-
Insulinoma / immunology
-
Insulinoma / therapy*
-
Macrophages / physiology*
-
Macrophages / radiation effects
-
Melanoma / immunology
-
Melanoma / therapy
-
Mice
-
Mice, Inbred C3H
-
Mice, Inbred NOD
-
Mice, SCID
-
Mice, Transgenic
-
Neoplasm Transplantation
-
Nitric Oxide Synthase Type II / metabolism*
-
Pancreatic Neoplasms / blood supply
-
Pancreatic Neoplasms / immunology
-
Pancreatic Neoplasms / therapy*
-
Phenotype
-
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
-
Radiotherapy Dosage
-
Radiotherapy, Adjuvant
-
Tumor Escape
-
Vaccination
Substances
-
Inflammation Mediators
-
Platelet Endothelial Cell Adhesion Molecule-1
-
NOS2 protein, human
-
Nitric Oxide Synthase Type II