Expression of NF-κB p50 in Tumor Stroma Limits the Control of Tumors by Radiation Therapy

Abstract

Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFκB p50, and that in mice lacking NFκB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specific adaptive immune responses, the intrinsic processes of repair following radiation therapy may limit the ability to control residual disease.

TGFβ Inhibition Prior to Hypofractionated Radiation Enhances Efficacy in Preclinical Models

“…Nevertheless, a decrease in the proportion of immune-suppressive myeloid cells mediated by TGFb inhibition could be a positive change in the tumor immune environment (45), as myeloid depletion has been shown to improve the response to radiotherapy (46). To determine whether this change in the tumor immune environment improved the efficacy of radiotherapy, mice were injected with Panc02 cells, then treated with control chow or SM16 chow for 1 week, and on day 14, mice underwent 20 Gy of radiotherapy daily for 3 consecutive days, totaling 60 Gy (33). Chow was discontinued before radiotherapy to minimize the effects on the postradiation immune environment.…”

“…Radiation was delivered using the clinical linear accelerator (6 MV photons; Elekta Synergy linear accelerator), with a halfbeam block to protect vital organs and 1.0-cm bolus. For CT26 tumors, 20 Gy  1 was delivered on day 14; for Panc02 tumors, 20 Gy  3 was delivered from day 14 to day 16, as described previously (33). Mice cured of CT26 tumors were rechallenged with 5  10 4 4T1 and 1  10 4 CT26 cells in opposite flanks to assess tumor-specific immunity.…”

“…Tumors were harvested on day 14 and homogenized into RIPA buffer (Sigma) containing protease inhibitors. Bone marrow-derived macrophages were obtained as described previously (33). Equal amounts of protein were separated on a 10% SDS-PAGE gel, transferred to a nitrocellulose membrane, blocked, and incubated overnight at 4 C with primary antibodies.…”

Anxiety and Framing Effects on Decision Making: Insights from Neuroimaging

“…The positive correlation between anxiety and amygdala activation during frame-consistent decisions supports the first explanation, as the amygdala plays a pivotal role in the processing of and response to emotional stimuli. However, it is interesting to note that the correlation between trait anxiety and brain activation during frame-inconsistent decisions seems indicative of an effort-related effect: this activation map (including the ACC, supplementary motor area, anterior insula, and lateral frontal and parietal regions) resembles the activation pattern that is typically observed during cognitively demanding conditions, e.g., in cognitivecontrol paradigms (Crittenden et al, 2012;Power and Petersen, 2013). This supports the idea that for highly anxious individuals it requires more cognitive effort to make decisions that run counter to the frame, rendering them more likely to rely on heuristics such as the use of easily accessible information provided by the framing context.…”

Role of Activin A in Immune Response to Breast Cancer

“…There are reports that RT can impair DC function, including cross-priming (109,110). Additionally, RT can contribute to the immunesuppressive tumor microenvironment by recruiting MDSCs and TAMs (76,(111)(112)(113). Tumor-infiltrating Tregs are also enriched after RT (77,114).…”