Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment

Abstract

In recent decades, there has been substantial growth in our understanding of the immune system and its role in tumor growth and overall survival. A central finding has been the cross-talk between tumor cells and the surrounding environment or stroma. This tumor stroma, comprised of various cells, and extracellular matrix (ECM), has been shown to aid in suppressing host immune responses against tumor cells. Through immunosuppressive cytokine secretion, metabolic alterations, and other mechanisms, the tumor stroma provides a complex network of safeguards for tumor proliferation. With recent advances in more effective, localized treatment, radiation therapy (XRT) has allowed for strategies that can effectively alter and ablate tumor stromal tissue. This includes promoting immunogenic cell death through tumor antigen release to increasing immune cell trafficking, XRT has a unique advantage against the tumoral immune evasion mechanisms that are orchestrated by stromal cells. Current studies are underway to elucidate pathways within the tumor stroma as potential targets for immunotherapy and chemoradiation. This review summarizes the effects of tumor stroma in tumor immune evasion, explains how XRT may help overcome these effects, with potential combinatorial approaches for future treatment modalities.

Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma

“…Rich in cancer-associated fibroblasts, MDSCs, protumor growth M2 macrophages, and Tregs, 12 these components of the stroma function collectively to mediate treatment resistance and facilitate tumor progression. 13 We further hypothesize that low-dose radiation (L-XRT) directed to secondary tumors, delivered in combination with immunotherapy and H-XRT to primary tumors, can modify the stroma so as to enhance systemic antitumor benefits. We hereby showed that L-XRT treatment resulted in increased proportions of effector immune cells in the transplanted lung cancer murine tumors.…”

microRNAs identified in prostate cancer: Correlative studies on response to ionizing radiation

“…All these components that make up the TME components are known to be affected by IR and may therefore modulate therapeutic response [19,105]. In response to IR, the TME can promote immunogenic cell death through tumor antigen release [106] and induce vascular remodeling to improve radiotherapy efficiency [14], while conversely IR can also induce radioresistance through the promotion of EMT [107]. miRNAs are known to be involved in regulating the TME and radiotherapy response [108,109].…”

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

“…Irradiated tumor cells would also undergo immunogenic cell death with the release of tumor antigens and various danger-associated molecular patterns (DAMPs) molecules [ 87 , 88 ]. This immunogenic cell death will further increase the process of immune recognition by antigen presenting cells, as discussed above.…”