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.
Highlights
There exists an array of cytotoxic therapies that can dramatically reduce the tumor to only a few cells with clonogenic potential
To investigate the efficacy of radiation therapy on cancer cells, tumors were harvested from mice bearing Panc02 tumors 1 day or 7 days following the final dose of radiation and cancer cell viability determined by clonogenic assay (Figure 1A)
To examine the consequence of radiation-induced cancer cell death on tumor macrophages, we harvested tumors from mice bearing Panc02 tumors 1 day or 7 days following the final dose of radiation and performed flow cytometry on tumor-infiltrating cells
Summary
There exists an array of cytotoxic therapies that can dramatically reduce the tumor to only a few cells with clonogenic potential. Catastrophic death of cancer cells can result in release of endogenous immune adjuvants that can alter immune responses, such as heat shock proteins, calreticulin and HMGB1 [2,6]. Studies demonstrate that expression of TLR4, a key receptor for immunological adjuvants, is critical both for vaccination with tumor cells killed via radiation or chemotherapy, and the efficacy of cytotoxic therapy in vivo [8]. These data fit a model where adjuvants released from dying cancer cells may play a role in establishing functional anti-tumor immune responses
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