Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy

Abstract

Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the "in situ" vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.

Keywords: hypoxia; immunosuppression; radioresistance; radiotherapy; tumor microenvironment; tumor vasculature; “in situ” vaccination.

Figure 1

Tumor microenvironment (TME). TME is a functional and structural niche where tumor progression occurs. It consists of cellular and molecular (extracellular matrix, cytokines, chemokines, and other molecules) components. The microenvironment is composed of tumor stromal cells (cancer-associated fibroblast (CAFs), mesenchymal stromal cells (MSCs), endothelial cells (ECs), pericytes) and immune cells (T cells, B cells, natural killer (NK) cells, dendritic cells (DCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs)) [6]. The cells differ in radiosensitivity. The term “radiosensitivity” means the relative susceptibility of cells to radiotherapy (RT)-induced irreversible damage such as chromosomal instability and cell death [37]. (A) Proliferating tumor cells are sensitive to irradiation (IR) [37]. Endothelial cells are resistant to doses up to 10Gy. CAFs are the most resistant stromal cells. (B) Within the cells of the immune system regulatory T cells (Tregs) are more radioresistant than any other population of T cells [38] and B cells [39]. NK cells and B lymphocytes are the most radiosensitive immune cells, while DCs are the most resistant [40].

Figure 2

The effect of various doses of radiotherapy (RT) on the components of the tumor microenvironment. Radiation doses affect the cancer cells and the surrounding tumor microenvironment differently, including tumor vascularization, immune system cells, and CAFs. Low doses (Low-dose radiation, LDR) induce mainly apoptosis in cancer cells, with tolerogenic or immunogenic cell death. APCs are not activated, immunosuppressive macrophages TAM M2 and MDSCs are recruited. In some cases, TAMs may be polarized towards M1, and CD8+ and CD4+ T lymphocyte infiltration may be increased. However, the activated anticancer response is insufficient. ECs survive low IR doses, and angiogenesis/vasculogenesis is stimulated. During fractionated radiotherapy, “tumor reoxygenation” may occur, which leads to an increase in the effectiveness of RT. Intermediate-dose radiation (IDR) induces tumor cell death without increasing hypoxia or immunosuppression. MHC-I up-regulation, antigen presentation by DCs, reduced levels of MDSCs or Tregs, and transient induction of environmental proinflammatories occur. The vessels may be normalized, and perfusion, oxygenation, and the number of pericytes may be increased. IDR can also induce the process of angiogenesis or vasculogenesis. High-dose radiation (HDR) induces necrosis of tumor cells, and immunogenic cell death associated with the release of TAAs and DAMPs. An effective antitumor immune response is activated. ECs undergo apoptosis or senescence. Tumor vascularization is destroyed. Increased areas of hypoxia lead to an immunosuppressive environment. New vessels are formed in the process of vasculogenesis. CAFs also undergo a senescence process. They secrete a number of SASP factors involved in fibrosis and TME modulation. The effect of doses on tumor vascularization or immune system reactions is not entirely clear. There are conflicting literature reports. This is related to the fact that there is a delicate balance between the activation and inhibition of the immune system induced by RT. Further research into TME mechanisms triggered by various RT doses is necessary. TAA, tumor-associated antigens; DAMPs, death-associated molecular patterns; MVD, microvessel density; TGF-β, transforming growth factor-β; MHC-I, major histocompatibility complex I; LNs, lymph nodes; BM-DC, bone-marrow-derived dendritic cell; SASP, senescence-associated secretory phenotype.