Radiation-Induced IFN-γ Production within the Tumor Microenvironment Influences Antitumor Immunity

Abstract

Alterations to the tumor microenvironment following localized irradiation may influence the effectiveness of subsequent immunotherapy. The objective of this study was to determine how IFN-γ influences the inflammatory response within this dynamic environment following radiotherapy. B16/OVA melanoma cells were implanted into C57BL/6 (wild-type (WT)) and IFN-γ-deficient (IFN-γ−/−) mice. Seven days after implantation, mice received 15 Gy of localized tumor irradiation and were assessed 7 days later. Irradiation up-regulated the expression of VCAM-1 on the vasculature of tumors grown in WT but not in IFN-γ−/− mice. Levels of the IFN-γ-inducible chemokines MIG and IFN-γ-inducible protein 10 were decreased in irradiated tumors from IFN-γ−/− mice compared with WT. In addition to inducing molecular cues necessary for T cell infiltration, surface MHC class I expression is also up-regulated in response to IFN-γ produced after irradiation. The role of IFN-γ signaling in tumor cells on class I expression was tested using B16/OVA cells engineered to overexpress a dominant negative mutant IFN-γ receptor (B16/OVA/DNM). Following implantation and treatment, expression of surface class I on tumor cells in vivo was increased in B16/OVA, but not in B16/OVA/DNM tumors, suggesting IFN-γ acts directly on tumor cells to induce class I up-regulation. These increases in MHC class I expression correlated with greater levels of activated STAT1. Thus, IFN-γ is instrumental in creating a tumor microenvironment conducive for T cell infiltration and tumor cell target recognition.

Priming anti-tumor immunity by radiotherapy: Dying tumor cell-derived DAMPs trigger endothelial cell activation and recruitment of myeloid cells

“…6,15–17 Investigations in different mouse tumor models revealed that radiotherapy-induced anti-tumor immune reactions, which are essentially dependent on type-I interferons (produced by the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) axis), APCs, and cytotoxic CD8 + T cells, are exclusively stimulated by high single doses (10–20 Gy). 18–23 On the contrary, a recent study suggests that 3 × 8 Gy may be optimal. 24 Clinically, abscopal tumor lesion regression remains rare, most likely because comparable super-hypofractionated protocols (fractions of >5 Gy) are rarely used in the radiotherapeutic routine.…”

The Effects of Epidural Anaesthesia and Analgesia on Natural Killer Cell Cytotoxicity and Cytokine Response in Patients with Epithelial Ovarian Cancer Undergoing Radical Resection

“…35 IFN-γ has important effects in the tumour microenvironment, including the inhibition of cell proliferation and angiogenesis. 33 Investigations have revealed that epidural anaesthesia and spinal block may influence cytokine responses and inhibit tumour metastasis. 4,36 The present study showed higher serum concentrations of antitumourigenic IL-10 and IFN-γ, and lower serum concentrations of protumourigenic IL-1β and IL-8 at T 4 h , in patients who received combined general/epidural anaesthesia.…”

“…32 In contrast, both IL-10 and IFN-γ are well known antitumour cytokines. 33,34 IL-10 exhibits antitumour and antimetastatic activity through enhanced NK cell lysis of tumour cells. 35 IFN-γ has important effects in the tumour microenvironment, including the inhibition of cell proliferation and angiogenesis.…”

On the kinetic Fokker-Planck equation in the half-space with absorbing barriers

“…Multiple smaller doses of radiation instead of the single dose were ineffective in slowing tumor growth, and chemotherapy administered after the single dose interfered with tumor regression and the associated immune response (4). Additional studies showed that radiation exposure increased tumor immunogenicity, stimulated antigen-presenting cells and promoted migration and entry of T cells into tumors (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

“…In addition, radiation can be used to enhance systemic T-cell antitumor immunity that can improve therapeutic efficacy (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Recent studies have shown that the ability of a single dose of radiation (20 Gy) to slow the growth of primary melanoma tumors is dependent on immune cells, since the slowing observed in wild-type mice failed to occur in immunodeficient nude mice, and slowing was abrogated by depleting the CD8 þ T cells of the tumor-bearing mice with monoclonal antibodies (4,5).…”