Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy

• Published in: International journal of molecular sciences Vol. 20; no. 13; p. 3212
• Main Authors: Jarosz-Biej, Magdalena, Smolarczyk, Ryszard, Cichoń, Tomasz, Kułach, Natalia
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29-06-2019; MDPI
• Subjects: Adaptive immunity; Adenosine triphosphate; Angiogenesis; Antigen presentation; Antigens; Apoptosis; ATP; Calreticulin; Cancer therapies; CD8 antigen; CD80 antigen; CD86 antigen; CD95 antigen; Cell activation; Cell differentiation; Cell surface; Chemokines; Colony-stimulating factor; CTLA-4 protein; Cytokines; Cytotoxicity; Dendritic cells; Endothelin 1; Endothelin 2; Fas antigen; Growth factors; Heat shock proteins; Hypoxia; Immune system; Immunology; immunosuppression; Inflammation; Irradiation; Ligands; Lymphatic system; Lymphocytes; Lymphocytes T; Macrophages; Metastases; Metastasis; Monocyte chemoattractant protein 1; PD-1 protein; Polypeptides; Proteins; Radiation therapy; radioresistance; radiotherapy; Review; tumor microenvironment; tumor vasculature; Tumors; Vascular endothelial growth factor; γ-Interferon; “in situ” vaccination; hypoxia; radiotherapy; immunosuppression; tumor microenvironment; tumor vasculature; “in situ” vaccination; radioresistance
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20133212

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.