Validating the pivotal role of the immune system in low‐dose radiation‐induced tumor inhibition in Lewis lung cancer‐bearing mice

Abstract

Although low‐dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR‐induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high‐dose radiation (HDR) of 1 Gy. Additionally, the LDR‐induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR‐activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR‐induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice.

Complex interplay between tumor microenvironment and cancer therapy

“…Treatment of eribulin mesylate, which is a tubulin binding drug, inhibits tumor progression by increasing the vessels density and NK cell infiltration in TME [8]. Similarly, tumor irradiation could induce damage responses that change the predominant TME cytokine profile toward an immunostimulatory profile, leading to the immunogenic cell death of cancer cells [7,95].…”

Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma

“… 14 In another study, very-low-dose (four fractions of 75 mGy each) total body irradiation given 1 day before four fractions of 1 Gy each was shown to activate T cells and natural killer (NK) cells and to retard tumor growth in a Lewis lung carcinoma (LLC). 10 Finally, in a pancreatic carcinoma model, L-XRT (2 Gy) led to polarization of M2 macrophages into the M1 phenotype via production of induced nitric oxide synthase. This in turn augmented the infiltration of adoptively transferred TCRCD8 + T cells.…”

“…Indeed, we found in another series of studies that adding an inhibitor of indoleamine 2,3-dioxygenase 1 led to suppression of MDSCs, increased CD8 + T cell infiltration, and retarded tumor growth and metastasis in a model of anti-PD1-resistant lung cancer. 10 Moreover, combining H-XRT with anti-glucocorticoid-induced TNFR-related protein (GITR), led to the depletion of Tregs at the primary tumor site, increased the numbers of CD4 + and CD8 + cells and effector memory on tumor rechallenge, and led to pronounced abscopal effects in half of the mice so treated. 11 Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to more robust and lasting antitumor responses.…”

Low-Dose Total Body Irradiation Can Enhance Systemic Immune Related Response Induced by Hypo-Fractionated Radiation

“…Low-dose irradiation approach, defined as ≤0.2Gy at low linear energy transfer (LET) or ≤0.05Gy at high LET, is known to induce both innate and adaptive anti-tumor immune responses (15, 16). It can activate T-cells and natural killer (NK) cells and increase T-cell proliferation, while reducing the infiltration of the immunosuppressive regulatory T-cell (Treg) in tumor tissues (17, 18).…”