Effects of a Unique Combination of the Whole-Body Low Dose Radiotherapy with Inactivation of Two Immune Checkpoints and/or a Heat Shock Protein on the Transplantable Lung Cancer in Mice

Abstract

Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer death worldwide. Recently, targeting molecules whose functions are associated with tumorigenesis has become a game changing adjunct to standard anti-cancer therapy. As evidenced by the results of preclinical and clinical investigations, whole-body irradiations (WBI) with X-rays at less than 0.1–0.2 Gy per fraction can induce remissions of various neoplasms without inciting adverse side effects of conventional chemo- and radiotherapy. In the present study, a murine model of human NSCLC was employed to evaluate for the first time the anti-neoplastic efficacy of WBI combined with inactivation of CTLA-4, PD-1, and/or HSP90. The results indicate that WBI alone and in conjunction with the inhibition of the function of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the programmed death-1 (PD-1) receptor immune checkpoints (ICs) and/or heat shock protein 90 (HSP90) markedly reduced tumorigenesis in mice implanted by three different routes with the syngeneic Lewis lung cancer cells and suppressed clonogenic potential of Lewis lung carcinoma (LLC1) cells in vitro. These results were associated with the relevant changes in the profile of pro- and anti-neoplastic immune cells recruited to the growing tumors and the circulating anti- and pro-inflammatory cytokines. In contrast, inhibition of the tested molecular targets used either separately or in combination with each other did not exert notable anti-neoplastic effects. Moreover, no significant synergistic effects were detected when the inhibitors were applied concurrently with WBI. The obtained results supplemented with further mechanistic explanations provided by future investigations will help design the effective strategies of treatment of lung and other cancers based on inactivation of the immune checkpoint and/or heat shock molecules combined with low-dose radiotherapy.

Can Low-Level Ionizing Radiation Do Us Any Harm?

“…In all these cases, five consecutive irradiations of mice at 0.02 or 0.2 Gy of X-rays per day significantly suppressed the growth of murine tumour cells, either in the lungs (Figure 2) or under the skin (data not shown). 55 Similar results were also obtained in tumour-bearing rats. In a study conducted at the Hokkaido University School of Medicine in Sapporo, Japan, WKHA rats were subcutaneously implanted with allogeneic KDH-8 hepatoma cells (which metastasize to the lungs) and 14 days later irradiated at 0.2 Gy by X-rays; the radiation was delivered either to the whole body or only to the site of tumour implantation.…”

“…*indicates statistically significant (p > 0.05) difference against the result obtained in the control (0 Gy) group (modified, after Ref. 55). …”

“…In all these cases, five consecutive irradiations of mice at 0.02 or 0.2 Gy of X-rays per day significantly suppressed the growth of murine tumour cells, either in the lungs (Figure 2) or under the skin (data not shown). 55

Figure 1.Development of neoplastic colonies in the lungs of mice treated with single exposures of X-rays at 0.1, 0.2 or 1.0 Gy, compared to the control rate (100%) observed in the unexposed mice. Shown are results of three independent experiments; *indicates significant (p < 0.05) difference against the control value (modified, after Ref.

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Low-dose radiotherapy encourages the generation of IFN and improves the tumor immune microenvironment

“…IRF7's impact on type I IFN regulation leads to immune microenvironment shifts, from immunosuppressive to anti-tumor dominance (38). However, IRF7's behavior is context-dependent, as it can exhibit both tumor-promoting and tumor-suppressing properties, depending on the speci c tumor-associated immune system (TAIS) dynamics (39)(40)(41)(42)(43)(44)(45).…”

Application of individualized multimodal radiotherapy combined with immunotherapy in metastatic tumors

“…Nowosielska et al. ( 196 ) found that LDRT to the whole-body (0.1 or 1.0 Gy) combined with anti-CTLA-4 antibody and anti-PD-1 antibody and NVP-AUY922 significantly reduced tumorigenesis in mice, and inhibited the clonogenic potential of Lewis lung cancer cells in vitro . By using targeted radionuclide therapy to semi-selectively deliver radiation to mouse tumors, Patel et al.…”