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

SIMPLE SUMMARY: The immune system represents an important link for tumor development, tumor control and tumor progression. The tumor immunogenic balance, determined by the prevalently immuno-inhibitory tumor- and conventional radiation-related effects is shifted negatively towards immunosuppression, which can worsen treatment outcome and prognosis. Emerging evidence suggest that those suppressive effects might be converted to an immunostimulative environment that can improve the therapeutic ratio with uses of newer conventional radiotherapy approaches combined with emerging immunotherapy agents. 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.