Biology of NSCLC: Interplay between Cancer Cells, Radiation and Tumor Immune Microenvironment

Abstract

The overall prognosis and survival of non-small cell lung cancer (NSCLC) patients remain poor. The immune system plays an integral role in driving tumor control, tumor progression, and overall survival of NSCLC patients. While the tumor cells possess many ways to escape the immune system, conventional radiotherapy (RT) approaches, which are directly cytotoxic to tumors, can further add additional immune suppression to the tumor microenvironment by destroying many of the lymphocytes that circulate within the irradiated tumor environment. Thus, the current immunogenic balance, determined by the tumor- and radiation-inhibitory effects is significantly shifted towards immunosuppression, leading to poor clinical outcomes. However, newer emerging evidence suggests that tumor immunosuppression is an “elastic process” that can be manipulated and converted back into an immunostimulant environment that can actually improve patient outcome. In this review we will discuss the natural immunosuppressive effects of NSCLC cells and conventional RT approaches, and then shift the focus on immunomodulation through novel, emerging immuno- and RT approaches that promise to generate immunostimulatory effects to enhance tumor control and patient outcome. We further describe some of the mechanisms by which these newer approaches are thought to be working and set the stage for future trials and additional preclinical work.

Prognostic Value of Combing Primary Tumor and Nodal Glycolytic–Volumetric Parameters of 18F-FDG PET in Patients with Non-Small Cell Lung Cancer and Regional Lymph Node Metastasis

“…In addition, aged patients may experience more toxicities from anti-neoplastic agents and suffer more perioperative complications, which may increase treatment-related mortality [47]. Moreover, the function of the T-cell-mediated immune system declines with age and limits the cellular immune response against tumor cells in the elderly population, further explaining the unfavorable survival outcomes in patients with advanced age [48][49][50][51]. We also analyzed the effects of different histopathological types on survival.…”

Exploring the optimal dose of low ionizing radiation to enhance immune function: a rabbit model

“…The spleen contains a variety of mature lymphocytes and is involved in the immune response, and the spleen reflects the immune function of the body to a certain extent. 23–26 In this study, after low ionizing radiation, the cell proliferation kinetics in rabbits changed, and the proliferation characteristics changed adaptively. The cell cycle may subsequently be shortened and proliferation may be accelerated.…”

The Role of Tumor-Derived Exosomes in the Abscopal Effect and Immunotherapy

“…By inducing apoptosis of neutrophils and removing dead neutrophils [ 72 ], microenvironment homeostasis and anti-inflammatory effects could be achieved. Besides, several recent animal studies suggested that the combination of radiotherapy and immune checkpoint inhibitors like anti-PD-L1 was more efficient [ 73 ]. Radiotherapy activates the AbE first: when PD-1 on activated CD8+ T cells binds to the PD-L1 from TEX carried by APC, it inactivates CD8+ T cells utilizing anti-PD1 antibodies, which facilitates the maintenance of CD8+ T cell activation [ 74 ].…”

“…Radiotherapy activates the AbE first: when PD-1 on activated CD8+ T cells binds to the PD-L1 from TEX carried by APC, it inactivates CD8+ T cells utilizing anti-PD1 antibodies, which facilitates the maintenance of CD8+ T cell activation [ 74 ]. In addition, although some studies have supported this view, others have suggested that the therapeutic effect of the combination of these two therapies is related to the dose of radiation [ 75 , 76 ] and different types of radiotherapy, like stereotactic body radiotherapy (SBRT) [ 73 ], and for different tumors, the dose of radiotherapy that could achieve the best therapeutic effect was different [ 76 ]. However, there are some different results in other studies and clinical trials.…”