Radiotherapy (RT) is the standard of care for cancer. In modern clinical practice, 3D-conformal radiotherapy (CRT) is used, which allows the most accurate impact on the tumor with high doses of radiation without affecting healthy tissues.
CRT minimizes radiotherapy’s short- and long-term side effects, including gastrointestinal damage, chronic pneumonitis, cardiotoxicity, cognitive impairment, and impaired bone growth. In addition, CRT is more effective than conventional radiation therapy, and the type I interferon response contributes to the therapeutic effect.
The effect of radiotherapy depends on the activation of monocytes.
In addition to direct toxic effects on cancer cells, radiation therapy induces monocyte infiltration into the tumor microenvironment (TME) and can have both immunostimulatory and immunosuppressive effects. What will be the effect of radiation therapy depends on the activation of monocytes affected by type I interferon.
Immunostimulating Effect of Radiotherapy
The death of tumor cells stimulates the production of interferon type I (IFN-I). IFN-I contributes to the launch of the systemic antitumor immune response. Monocyte infiltration into the tumor contributes to the therapeutic effect of radiation therapy. Monocytes can secrete IFN-I and respond to it. The IFN-I response increases the ability of monocytes to activate CD8+ T cells, which destroy the tumor.
Immunosuppressive Effects of Radiotherapy
Accumulation and activation of monocytes in tumors are disrupted when radiation therapy affects healthy tissue. In addition, if monocyte recruitment and function are blocked, focal radiotherapy may become less effective.
Type I interferon signaling is required for monocyte activation. Monocytes accumulate in the TME 1 day after CRT. If conventional radiation therapy has been performed, monocytes are redistributed between TME and irradiated healthy tissues. Therefore, lower levels of IFN-I are observed in tumors after conventional radiotherapy. A low level of IFN-I-secreting monocytes leads to monocytes’ acquisition of immunosuppressive functions. These immunosuppressive monocytes reduce the efficacy of radiotherapy.
RT And CRT Differs in Monocyte Activation
After RT, tumor-infiltrating monocytes acquire immunosuppressive properties. However, monocytes acquire immunostimulatory functions after CRT. These immunostimulatory functions depend on the ability of monocytes to respond to IFN-I. Type I interferon stimulates monocytes to produce T-cell-activating cytokines that destroy the tumor.
Conclusion
The less radiotherapy affects healthy tissues, the more effective it is. Radiation therapy causes a rapid and robust infiltration of monocytes. If healthy tissues are not irradiated, monocytes acquire immunostimulatory properties and activate CD8+ T cells, which destroy the tumor. Monocyte activation requires type I interferon.
Radiation exposure to healthy organs is inevitable during radiotherapy of tumors localized in internal organs such as the prostate, chest, lungs, stomach, and brain. Strategies that reduce radiation damage to healthy tissue will help improve the outcome of internal radiation therapy.
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Reference
Rapid recruitment and IFN-I–mediated activation of monocytes dictate focal radiotherapy efficacy
