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Review
. 2023 Aug 4;15(15):3972.
doi: 10.3390/cancers15153972.

Innate Immune System in the Context of Radiation Therapy for Cancer

Affiliations
Review

Innate Immune System in the Context of Radiation Therapy for Cancer

Ettickan Boopathi et al. Cancers (Basel). .

Abstract

Radiation therapy (RT) remains an integral component of modern oncology care, with most cancer patients receiving radiation as a part of their treatment plan. The main goal of ionizing RT is to control the local tumor burden by inducing DNA damage and apoptosis within the tumor cells. The advancement in RT, including intensity-modulated RT (IMRT), stereotactic body RT (SBRT), image-guided RT, and proton therapy, have increased the efficacy of RT, equipping clinicians with techniques to ensure precise and safe administration of radiation doses to tumor cells. In this review, we present the technological advancement in various types of RT methods and highlight their clinical utility and associated limitations. This review provides insights into how RT modulates innate immune signaling and the key players involved in modulating innate immune responses, which have not been well documented earlier. Apoptosis of cancer cells following RT triggers immune systems that contribute to the eradication of tumors through innate and adoptive immunity. The innate immune system consists of various cell types, including macrophages, dendritic cells, and natural killer cells, which serve as key mediators of innate immunity in response to RT. This review will concentrate on the significance of the innate myeloid and lymphoid lineages in anti-tumorigenic processes triggered by RT. Furthermore, we will explore essential strategies to enhance RT efficacy. This review can serve as a platform for researchers to comprehend the clinical application and limitations of various RT methods and provides insights into how RT modulates innate immune signaling.

Keywords: DNA damage; NK cells; dendric cells; hypoxia; macrophages; microbubble oxygen; radiation therapy; tumor microenvironment.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Figure 1
Figure 1
Overview of Different Types of Radiation Therapy: (A) The diagram depicts external beam radiation therapy. (B 13) The cartoon presents different models of internal beam radiation therapy: (B 1) Schematics show a thyroid patient being treated with radioactive iodine-131 medication. (B 2) Indicated radioactive capsules are embedded near or inside the tumor in breast, skin, gynecological and prostate cancer. (B 3) Cartoon shows the delivery of indicated radioactive beads/seeds in liver and lung cancers via a catheter.
Figure 2
Figure 2
Presence of Innate immune systems in the peripheral blood. (A) Liquid biopsy shows the normal count of macrophage, mast cell, basophil, eosinophil, monocyte, NK cell and dendric cells in the peripheral blood. (B) Liquid biopsy from cancer patients treated with RT shows reduced counts of macrophage, mast cell, basophil, eosinophil, monocyte, NK cell and dendric cells in the peripheral blood in response to RT-induced toxicity and bystander effects.
Figure 3
Figure 3
Direct and Indirect Effects of Radiation in Nuclear and Mitochondrial DNA from Tumor Cells. (A) The diagram presents the RT-induced apoptosis in tumor cells via direct single and double-strand breaks in nuclear and mitochondrial DNA. (B) The diagram represents the step-by-step RT-induced production of reactive oxygen species (ROS)/free radicles, which in turn promotes single and double-strand breaks in nuclear and mitochondrial DNA. While repaired single and double-strand DNA breaks can lead to tumor relapse or failure in DNA damage repair that can lead to cellular apoptosis and restricts disease-free survival among cancer patients, on the other hand, RT-induced apoptosis increases the disease-free survival rates among cancer patients. ? indicates may or may not happen, up-arrow indicates the increased survival and disease progression. The down arrow indicates poor survival.
Figure 4
Figure 4
Effect of Ionizing Radiation on Innate Immune Activation. (A) The illustration shows the low dose of fractionated RT induces the production of ROS, cytokines, chemokines, and damage-associated molecular patterns (DAMPs) from cancer cells, DAMPs promoting the activation of innate immune dendritic cells, nature killing cells (NK cells) and macrophages. Activated dendric cells present tumor antigens and are primed for T-cell activation. Activated NK cells promote cytotoxic effects on tumor cells, and activated macrophages destroy cancer cells via active phagocytosis. (B) The cartoon illustration shows that a high dose of unfractionated radiation induces the production of ROS and DAMPs from cancer cells, inactivating innate immune dendritic cells, macrophages, and NK cells, promoting immune escape and tumor relapse. Unfractionated radiation also promotes adaptive immune cell activation via T-cells, NK cells and B-cells and promotes intra-tumoral immunity. ? indicates may or may not happen, arrow indicates the next step.
Figure 5
Figure 5
Proposed Therapeutic Option to Enhance the Efficacy of RT and Maintain the Innate Immunity. (A) The cartoon depicts tumor angiogenesis in response to indicated tumor microenvironment (TME) with all indicated immune cells. (B) Fractionated low doses of RT induce a partial response from tumors and innate immune systems. (C) The combination of both radioprotectors and microbubble oxygen with fractionated radiation promotes enhanced survival of immune systems, including macrophages, mast dendric, NK cells and tumor-infiltrating T-cell survival at the tumor site and increases the efficacy of radiation therapy.

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