Ex Vivo Irradiation of Lung Cancer Stem Cells Identifies the Lowest Therapeutic Dose Needed for Tumor Growth Arrest and Mass Reduction In Vivo

Abstract

Radiotherapy represents a first-line treatment for many inoperable lung tumors. New technologies offer novel opportunities for the treatment of lung cancer with the administration of higher doses of radiation in smaller volumes. Because both therapeutic and toxic treatment effects are dose-dependent, it is important to identify a minimal dose protocol for each individual patient that maintains efficacy while decreasing toxicity. Cancer stem cells sustain tumor growth, promote metastatic dissemination, and may give rise to secondary resistance. The identification of effective protocols targeting these cells may improve disease-free survival of treated patients. In this work, we evaluated the existence of individual profiles of sensitivity to radiotherapy in patient-derived cancer stem cells (CSCs) using both in vitro and in vivo models. Both CSCs in vitro and mice implanted with CSCs were treated with radiotherapy at different dose intensities and rates. CSC response to different radiation doses greatly varied among patients. In vitro radiation sensitivity of CSCs corresponded to the therapeutic outcome in the corresponding mouse tumor model. On the other side, the dose administration rate did not affect the response. These findings suggest that in vitro evaluation of CSCs may potentially predict patients’ response, thus guiding clinical decision.

Computational Approach for Spatially Fractionated Radiation Therapy (SFRT) and Immunological Response in Precision Radiation Therapy

“…Some preclinical and clinical evidence confirms the synergistic action of radiotherapy (RT) and immunotherapy against the tumor cells [14]. Although the intrinsic sensitivity to radiation is patient-specific [15,16] and may depend on different factors, RT is able to ablate cancer cells not only by directly induced necrosis or apoptosis but also by triggering an immune response that actively recruits immune cells within the tumor microenvironment. For example, RT promotes the release of tumor-associated antigens, which, once processed by antigen-presenting cells (APCs), prime CD8 + 4 T cells in the draining lymph nodes.…”

Dynamic alterations in PD-1/PD-L1 expression level and immune cell profiles based on radiation response status in mouse tumor model

“…Therefore, we would like to highlight that this is the first study to evaluate radiation-induced dynamic changes in PD-1/PD-L1-related immune cell profiles. Although each mouse-derived cancer cell line differs in terms of immunogenicity and radiosensitivity ( 35 ), we preferentially selected the CT26 cell line, which is radiosensitive and has highly immunogenic profile ( 36 ). The data of absolute numbers of tumor-infiltrating leukocytes may also be useful to assess the level of infiltration, but the relative changes in the expression level of PD-1/PD-L1, following RT, were determined as the primary outcome, regarding the scope of this study.…”

Mathematical modeling of the synergistic interplay of radiotherapy and immunotherapy in anti-cancer treatments

“…Some preclinical and clinical evidence confirm the synergistic action of radiotherapy (RT) and immunotherapy against the tumor cells Zhao and Shao (7). Although The intrinsic sensitivity to radiation is patient-specific Puglisi et al (8); Puglisi et al (9) and may depend on different factors, RT is able to ablate cancer cells not only by directly induced necrosis or apoptosis but also by triggering an immune response that actively recruits immune cells within the tumor microenvironment. For example, RT promotes the release of tumor-associated antigens, which, once processed by antigenpresenting cells (APCs), prime CD8 + and CD4 + T cells in the draining lymph nodes.…”

“…( 8 ); Puglisi et al. ( 9 ) and may depend on different factors, RT is able to ablate cancer cells not only by directly induced necrosis or apoptosis but also by triggering an immune response that actively recruits immune cells within the tumor microenvironment. For example, RT promotes the release of tumor-associated antigens, which, once processed by antigen-presenting cells (APCs), prime CD8 + and CD4 + T cells in the draining lymph nodes.…”