The interactions and communications in tumor resistance to radiotherapy: Therapy perspectives

https://doi.org/10.1016/j.intimp.2020.106807Get rights and content

Highlights

  • Radiotherapy can change the balance between tumor suppressing and tumor promoting cells.

  • The release of some chemokines such as CXCL9 and cytokines like IFN-γ and TNF-α can boost anti-tumor immunity.

  • The release of IL-10 and TGF-β as well as upregulation of immune checkpoints is critical mechanisms for tumor regrowth.

  • Boosting tumor promoting signaling and suppression of immune checkpoints potentiate anti-tumor immunity.

Abstract

Tumor microenvironment (TME) includes a wide range of cell types including cancer cells, cells which are involved in stromal structure and immune cells (tumor suppressor and tumor promoting cells). These cells have several interactions with each other that are mainly regulated via the release of intercellular mediators. Radiotherapy can modulate these interactions via shifting secretions into inflammatory or anti-inflammatory responses. Radiotherapy also can trigger resistance of cancer (stem) cells via activation of stromal cells. The main mechanisms of tumor resistance to radiotherapy is the exhaustion of anti-tumor immunity via suppression of CD4+ T cells and apoptosis of cytotoxic CD8+ T lymphocytes (CTLs). Cancer-associated fibroblasts (CAFs), mesenchymal-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are the main suppressor of anti-tumor immunity via the release of several chemokines, cytokines and immune suppressors. In this review, we explain the main cellular and molecular interactions and secretions in TME following radiotherapy. Furthermore, the main signaling pathways and intercellular connections that can be targeted to improve therapeutic efficiency of radiotherapy will be discussed.

Introduction

Cancer is one of the main causes of death worldwide. Estimates show that the incidence of cancer in most countries is growing and may be the first cause of death in future [1]. Presently, numerous researches are ongoing with a view to identifying the cellular and molecular basis of tumors, in order to provide improved cancer treatment strategies. Most patients undergo some common cancer therapy modalities such as radiotherapy, chemotherapy, hyperthermia and targeted therapy either alone or in combination [2]. In the recent decade, researchers in immunotherapy have developed some novel drugs to suppress tumors. This type of therapy may have less side effects compared to radiotherapy and chemotherapy [3], [4]. However, further studies investigating its therapeutic efficiency as well as possible late side effects are required in order to achieve effective clinical translation [5].

In contrast to chemotherapy which could give rise to systemic toxicity, radiotherapy kills cancer cells with lower side effects in distant tissues [6]. Some studies estimate that more than half of patients with solid tumors undergo radiotherapy either alone or in combination with other modalities [7]. Radiotherapy kills cancer cells not only directly. Classical dogma assumes that radiation kill cells through DNA damage via direct interaction or production of free radicals [8], [9]. An important weakness of this hypothesis is that it does not consider the role of other non-irradiated cells and intercellular communications that change their functions following exposure to radiation [10]. In normal tissues, changing redox metabolism and immune system function aggravate radiation toxicity. In fact, most side effects that we can observe after radiotherapy are because of this second reaction [11]. In tumors, changing the activity of other non-cancerous cells during or even after radiotherapy plays a key role in the fate of cancer cells [12].

Evidence have confirmed that intercellular communications between different cell types within tumor play a key role in the resistance or sensitization of cancer cells to chemotherapy drugs, radiation as well as immunotherapy [13]. Cells within tumor microenvironment (TME) can release tumor promoting or tumor suppressive molecules, depending on their communications [14], [15]. Radiotherapy has interesting properties for the control of released factors by tumor. This property can be used as an interesting agent to help sensitization and elimination of cancer cells [16]. Thus, in this review, the basic mechanisms of tumor response to radiotherapy and released mediators within TME will be discussed. Furthermore, we provide some information regarding tumor control through manipulation of communications within tumor during radiotherapy.

Section snippets

Cells and interactions within tumor microenvironment (TME)

TME includes a wide range of stromal and immune cells. In fact, cancer cells including cancer stem cells (CSCs), progenitor cancer cells and also differentiated cells are surrounded by various types of cells that affect their proliferation [17], [18]. Progression or regression of tumors is highly dependent on cells and interactions within TME [19]. Intercellular communications between cancer cells and CSCs with stroma and immune cells within TME can control the fate of tumor response to therapy

Immunogenic vs tolerogenic responses following radiotherapy

Initiation of immune system responses following radiotherapy occur due to DNA damage and cell death. Immune system reactions include both immunogenic and tolerogenic responses [27]. Immunogenic responses occur following immunogenic cell death. Necrosis is the most common type of immunogenic cell death. Necrosis occurs following massive damages to organelles, membrane and DNA [28]. An important property of necrosis that make it an immunogenic type of cell death is the outward release of contents

DAMPs in cancer (stem) cells resistance to radiotherapy

Some DAMPs including ADP and HMGB1 are able to trigger cancer cell responses. DAMPs, especially HMGB1 and adenosine can affect response of cancer cells and CSCs via suppression or activation of anti-tumor or pro-tumor cells within TME. Furthermore, these DAMPs can increase resistance of CSCs and cancer cells to apoptosis [44].

Tumor stroma in cancer (stem) cells resistance to radiation

Stroma of tumors provide a suitable situation for progression and invasion of cancer cells and CSCs [70]. Stroma of solid tumors include CAFs and other molecules such as collagen, fibronectin and fibrin, which provide a stiff space. Stiffness of tumors causes resistance against entrance of anti-cancer drugs and also infiltration of tumor suppressive cells including CTLs and NK cells [16]. In this section, we explain how tumor stroma increase resistance of cancer cells and CSCs to radiation.

Interactions between immune cells and cancer (stem) cells

There are several interactions within immune cells in TME, which play a central role in cancer cells and CSCs resistance to therapy. It seems that the fight between tumor promoting and anti-tumor cells determine the fate of cancer therapy [85], [86]. Cytokines, chemokines, exosomes and some other intercellular mediators play a central role in tumor growth or regression. Tumor-associated macrophages (TAMs), Tregs and MDSCs are the main pro-tumor cells. On the other hand, CTLs and NK cells cause

Targeting intercellular communications in combination with radioimmunotherapy

One of the most interesting strategies for tumor eradication is targeting the communications between cancer cells, stroma and immune cells [138]. As mentioned, high doses per fraction such as seen in SBRT can trigger immune system against cancer. Interestingly, activation of immune system against cancer is more effective compared to direct killing of cancer cells by ionizing radiation. Thus, the combination of radiotherapy and immunotherapy may be the best combination modality for the treatment

Conclusion

Besides cancer cells, TME includes tumor promoting and tumor suppressive cells. The interactions within TME favours the progression and growth of tumors. Radiotherapy can change the balance between tumor suppressing and tumor promoting cells. However, there are evidence that tumors provide some mechanisms that lead to more progressive tumor responses. The selection of an appropriate technique is necessary in activating immunity against tumor and prevent tolerogenic responses as much possible

Fund

This study received no financial support.

Declaration of Competing Interes

Authors declare no conflict of interest.

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